Substituted pyrido[3,4-d]pyrimidines and pyrido[4,3-d]pyrimidines as p70S6K inhibitors

ABSTRACT

Novel azaquinazoline carboxamide derivatives of formula (I) 
                         
wherein W 1 , W 2 , W 3 , W 4 , R 1 , R 2 , R 3  and m which are defined above, are p70S6K inhibitor, and can be employed, inter alia, for the treatment of hyperproliferative disorders.

RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.15/227,638, which is a divisional application of U.S. application Ser.No. 14/432,618, which is a U.S. national stage application ofinternational application PCT/US2013/072141, filed on Nov. 27, 2013,which claims the benefit of U.S. Provisional application 61/731,075,filed on Nov. 29, 2012. The contents of the aforementioned applicationsare incorporated herein in their entireties by reference.

FIELD OF THE INVENTION

The present invention relates to compounds of formula (I)

wherein W¹, W², W³, W⁴, R¹, R², R³ and m have the meaning as describedbelow, and/or physiologically acceptable salts thereof. The compounds offormula (I) can be used as p70S6K inhibitors. Other aspects of theinvention include pharmaceutical compositions comprising the compoundsof formula (I), and the use of the compounds of formula (I) for thetreatment of hyperproliferative disorders.

BACKGROUND

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a wide variety of signaltransduction processes within the cell (Hardie, G. and Hanks, S. (1995)The Protein Kinase Facts Book. I and II, Academic Press, San Diego,Calif.). The kinases may be categorized into families by the substratesthey phosphorylate (e.g., protein-tyrosine, protein-serine/threonine,lipids, etc.). Sequence motifs have been identified that generallycorrespond to each of these kinase families (e.g., Hanks & Hunter, FASEBJ. 9: 576-596 (1995); Knighton et al., Science 253: 407-414 (1991);Hiles et al., Cell 70: 419-429 (1992); Kunz et al., Cell 73:585-596(1993); Garcia-Bustos et al., EMBO J. 13:2352-2361 (1994)).

Protein kinases may be characterized by their regulation mechanisms.These mechanisms include, for example, autophosphorylation,transphosphorylation by other kinases, protein-protein interactions,protein-lipid interactions, and protein-polynucleotide interactions. Anindividual protein kinase may be regulated by more than one mechanism.

Kinases regulate many different cell processes including, but notlimited to, proliferation, differentiation, apoptosis, motility,transcription, translation and other signaling processes, by addingphosphate groups to target proteins. These phosphorylation events act asmolecular on/off switches that can modulate or regulate the targetprotein biological function.

Phosphorylation of target proteins occurs in response to a variety ofextracellular signals (hormones, neurotransmitters, growth anddifferentiation factors, etc.), cell cycle events, environmental ornutritional stresses, etc. The appropriate protein kinase are involvedin signaling pathways to activate or inactivate (either directly orindirectly), for example, a metabolic enzyme, regulatory protein,receptor, cytoskeletal protein, ion channel or pump, or transcriptionfactor. Uncontrolled signaling due to defective control of proteinphosphorylation has been implicated in a number of diseases, including,for example, inflammation, cancer, allergy/asthma, diseases andconditions of the immune system, diseases and conditions of the centralnervous system, and angiogenesis.

Protein kinase 70S6K, the 70 kDa ribosomal protein kinase p70S6K (alsoknown as SK6, p70/p85 S6 kinase, p70/p85 ribosomal S6 kinase andpp70S6K), is a member of the AGC subfamily of protein kinases. p70S6K isa serine-threonine kinase that is a component of thephosphatidylinositol 3 kinase (PI3K)/AKT pathway. p70S6K is downstreamof PI3K, and activation occurs through phosphorylation at a number ofsites in response to numerous mitogens, hormones and growth factors.p70S6K activity is also under the control of a mTOR-containing complex(TORC1) since rapamycin acts to inhibit p70S6K activity. p70S6K isregulated by PI3K downstream targets AKT and PKCζ. Akt directlyphosphorylates and inactivates TSC2, thereby activating mTOR. Inaddition, studies with mutant alleles of p70S6K that are inhibited byWortmannin but not by rapamycin suggest that the PI3K pathway canexhibit effects on p70S6K independent of the regulation of mTORactivity.

The enzyme p70S6K modulates protein synthesis by phosphorylation of theS6 ribosomal protein. S6 phosphorylation correlates with increasedtranslation of mRNAs encoding components of the translational apparatus,including ribosomal proteins and translational elongation factors whoseincreased expression is essential for cell growth and proliferation.These mRNAs contain an oligopyrimidime tract at their 5′ transcriptionalstart (termed 5′TOP), which has been shown to be essential for theirregulation at the translational level.

In addition to its involvement in translation, p70S6K activation hasalso been implicated in cell cycle control, neuronal celldifferentiation, regulation of cell motility and a cellular responsethat is important in tumor metastases, the immune response and tissuerepair. Antibodies to p70S6K abolish the mitogenic response driven entryof rat fibroblasts into S phase, indicating that p70S6K function isessential for the progression from G1 to S phase in the cell cycle.Furthermore, inhibition of cell cycle proliferation at the G1 to S phaseof the cell cycle by rapamycin has been identified as a consequence ofinhibition of the production of the hyperphosphorylated, activated formof p70S6K.

A role for p70S6K in tumor cell proliferation and protection of cellsfrom apoptosis is supported based on its participation in growth factorreceptor signal transduction, overexpression and activation in tumortissues. For example, Northern and Western analyses revealed thatamplification of the PS6K gene was accompanied by correspondingincreases in mRNA and protein expression, respectively (Cancer Res.(1999) 59: 1408-11-Localization of PS6K to Chromosomal Region 17q23 andDetermination of Its Amplification in Breast Cancer).

Chromosome 17q23 is amplified in up to 20% of primary breast tumors, in87% of breast tumors containing BRCA2 mutations and in 50% of tumorscontaining BRCA1 mutations, as well as other cancer types such aspancreatic, bladder and neuroblastoma (cf. Barlund et al., Cancer Res.60: 5340-5346 (2000)). It has been shown that 17q23 amplifications inbreast cancer involve the PAT1, RAD51C, PS6K, and SIGMA1B genes (CancerRes. (2000): 60, pp. 5371-5375). The p70S6K gene has been identified asa target of amplification and overexpression in this region, andstatistically significant association between amplification and poorprognosis has been observed.

Clinical inhibition of p70S6K activation was observed in renal carcinomapatients treated with CCl-779 (rapamycin ester), an inhibitor of theupstream kinase mTOR. A significant linear association between diseaseprogression and inhibition of p70S6K activity was reported.

In response to energy stress, the tumor suppressor LKB1 activates AMPKwhich phosphorylates the TSC1/2 complex and enables it to inactivate themTOR/p70S6K pathway. Mutations in LKB1 cause Peutz-Jeghers syndrome(PJS), where patients with PJS are 15 times more likely to developcancer than the general population. In addition, ⅓ of lungadenocarcinomas harbor inactivating LKB1 mutations. p70S6K has beenimplicated in metabolic diseases and disorders. It was reported that theabsence of p70S6K protects against age- and diet-induced obesity whileenhancing insulin sensitivity. A role for p70S6K in metabolic diseasesand disorders such as obesity, diabetes, metabolic syndrome, insulinresistance, hyperglycemia, hyperaminoacidemia, and hyperlipidmia issupported based upon the findings.

Compounds described as suitable for p70S6K inhibition are disclosed inWO 03/064397, WO 04/092154, WO 05/054237, WO 05/056014, WO 05/033086, WO05/117909, WO 05/039506, WO 06/120573, WO 06/136821, WO 06/071819, WO06/131835, WO 08/140947, WO 10/093419, and WO 12/069146.

In part, aurora kinases modulate a cell's progression through the cellcycle and mitosis. Hallmarks of cancer cell physiology are pathologicalchanges to the normal progression through the cell cycle and mitosis. Ithas been documented that some compounds which inhibit aurora kinases arealso associated with impaired chromosome alignment, weakening of themitotic checkpoint, polyploidy, and subsequent cell death. Morespecifically, inhibition of Aurora B kinase has been shown to causeneutropenia as dose limiting toxicity in several clinical trials (Dar etal., Mol Cancer Ther 9: 268-278 (2010)). In addition, inhibition ofAurora B kinase can be an off target effect in ATP competitive kinaseinhibitors. These Aurora B kinase inhibitors would also be expected toshow neutropenia as dose limiting toxicity caused by aurora inhibitionand, therefore, have a limited therapeutic window. Moreover, some aurorakinase inhibitors can also induce polyploidy in normal mammaryepithelial cell cultures, thereby, raising the issue of adverselong-term clinical.

Therefore, it is expected that p70S6K inhibitors, which substantiallyspare or significantly reduce the inhibition of Aurora B kinase, holdspecial promise in the treatment of hyperproliferative diseases, such ascancer, by reducing neutropenia as dose limiting toxicity and, thereby,improving the therapeutic window for these compounds. Furthermore, it isexpected that p70S6K inhibitors, which also inhibit kinase Akt (upstreamof p70S6K in the PI3K pathway), provide more efficient PI3K pathwayshutdown (Choo et al., PNAS USA 105(45): 17414-9 (2008)), and allow forcapture of any Akt feedback loop activation (Tamburini et al., Blood111: 379-82 (2008)).

SUMMARY OF THE INVENTION

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments. It has been surprisingly found that the compounds accordingto the invention and salts thereof have very valuable pharmacologicalproperties while being well tolerated. In particular, they act as p70S6Kinhibitors and optionally, as Akt inhibitors.

In one aspect, the invention provides compounds of formula (I)

wherein

-   each W¹, W², W³, W⁴ is independently N or CH, wherein at least one    of W¹, W², W³ or W⁴ is N;-   R¹ is Ar or Het¹;-   each R², R⁴, R⁵ is independently Y;-   R³ is Y or —(CH₂)_(p)—NR⁴R⁵;-   R² and R³ together with the atoms to which each is attached, may    form —(CH₂)_(n)—NY—(CH₂)_(p);-   R⁴ and R⁵ together with the atoms to which each is attached, may    form —(CY₂)_(q)—;-   Y is H or A;-   A is unbranched or branched alkyl having 1-10 C atoms, in which 1-7    H atoms can be replaced independently from one another by Hal;-   Ar is an unsaturated or aromatic mono- or bicyclic carbocycle having    3-10 C atoms, which can be substituted by at least one substituent    selected from the group of Hal, A, OY, CN, COY, COOY, CONYY, NYCOY,    NYCONYY, SO₂Y, SO₂NYY, NYSO₂Y, NYY, NO₂, OCN, SCN, SH, optionally    substituted phenyl and Het¹;-   Het¹ is an unsaturated or aromatic mono- or bicyclic heterocycle    having 2-10 C atoms and 1-4 N, O and/or S atoms, which can be    substituted by at least one substituent selected from the group of    Hal, A, OY, CN, COY, COOY, CONYY, NYCOY, NYCONYY, SO₂Y, SO₂NYY,    NYSO₂Y, NYY, NO₂, OCN, SCN, SH, optionally substituted phenyl and    Het²;-   Het² is an optionally substituted, saturated, unsaturated or    aromatic monocyclic 5-6-membered heterocycle having 2-5 C atoms and    1-3 N, O and/or S atoms;-   Hal is F, Cl, Br or I;-   m is 0 or 1;-   each n or p is independently 0, 1, 2 or 3; and-   q is 2, 3, 4, 5 or 6;-   and/or a physiologically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

In the meaning of the present invention, the compound is defined toinclude pharmaceutically usable derivatives, solvates, prodrugs,tautomers, enantiomers, racemates and stereoisomers thereof, includingmixtures thereof in all ratios.

The term “pharmaceutically usable derivatives” is taken to mean, forexample, the salts of the compounds according to the invention and alsoso-called prodrug compounds. The term “solvates” of the compounds istaken to mean adductions of inert solvent molecules onto the compounds,which are formed owing to their mutual attractive force. Solvates are,for example, mono- or dihydrates or alkoxides. The invention alsocomprises solvates of salts of the compounds according to the invention.The term “prodrug” is taken to mean compounds according to the inventionwhich have been modified by means of, for example, alkyl or acyl groups,sugars or oligopeptides and which are rapidly cleaved in the organism toform the effective compounds according to the invention. These alsoinclude biodegradable polymer derivatives of the compounds according tothe invention, as described, for example, in Int. J. Pharm. 115, 61-67(1995). It is likewise possible for the compounds of the invention to bein the form of any desired prodrugs such as, for example, esters,carbonates, carbamates, ureas, amides or phosphates, in which cases theactually biologically active form is released only through metabolism.Any compound that can be converted in-vivo to provide the bioactiveagent (i.e. compounds of the invention) is a prodrug within the scopeand spirit of the invention. Various forms of prodrugs are well known inthe art and are described (e.g. Wermuth C G et al., Chapter 31: 671-696,The Practice of Medicinal Chemistry, Academic Press 1996; Bundgaard H,Design of Prodrugs, Elsevier 1985; Bundgaard H, Chapter 5: 131-191, ATextbook of Drug Design and Development, Harwood Academic Publishers1991). Said references are incorporated herein by reference. It isfurther known that chemical substances are converted in the body intometabolites which may where appropriate likewise elicit the desiredbiological effect—in some circumstances even in more pronounced form.Any biologically active compound that was converted in-vivo bymetabolism from any of the compounds of the invention is a metabolitewithin the scope and spirit of the invention.

The compounds of the invention may be present in the form of theirdouble bond isomers as pure E or Z isomers, or in the form of mixturesof these double bond isomers. Where possible, the compounds of theinvention may be in the form of the tautomers, such as keto-enoltautomers. All stereoisomers of the compounds of the invention arecontemplated, either in a mixture or in pure or substantially pure form.The compounds of the invention can have asymmetric centers at any of thecarbon atoms. Consequently, they can exist in the form of theirracemates, in the form of the pure enantiomers and/or diastereomers orin the form of mixtures of these enantiomers and/or diastereomers. Themixtures may have any desired mixing ratio of the stereoisomers. Thus,for example, the compounds of the invention which have one or morecenters of chirality and which occur as racemates or as diastereomermixtures can be fractionated by methods known per se into their opticalpure isomers, i.e. enantiomers or diastereomers. The separation of thecompounds of the invention can take place by column separation on chiralor nonchiral phases or by recrystallization from an optionally opticallyactive solvent or with use of an optically active acid or base or byderivatization with an optically active reagent such as, for example, anoptically active alcohol, and subsequent elimination of the radical.

The invention also relates to the use of mixtures of the compoundsaccording to the invention, for example mixtures of two diastereomers,for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.These are particularly preferably mixtures of stereoisomeric compounds.

The nomenclature as used herein for defining compounds, especially thecompounds according to the invention, is in general based on the rulesof the IUPAC-organization for chemical compounds and especially organiccompounds. The terms indicated for explanation of the above compounds ofthe invention always, unless indicated otherwise in the description orin the claims, have the following meanings:

The term “unsubstituted” means that the corresponding radical, group ormoiety has no substituents. The term “substituted” means that thecorresponding radical, group or moiety has one or more substituents.Where a radical has a plurality of substituents, and a selection ofvarious substituents is specified, the substituents are selectedindependently of one another and do not need to be identical. Eventhough a radical has a plurality of a specific-designated substituent(e.g. Y₂ or YY) the expression of such substituent may differ from eachother (e.g. methyl and ethyl). It shall be understood accordingly that amultiple substitution by any radical of the invention may involveidentical or different radicals. Hence, if individual radicals occurseveral times within a compound, the radicals adopt the meaningsindicated, independently of one another. In case of a multiplesubstitution, the radical could be alternatively designated with R′, R″,R″′, R″″ etc.

The terms “alkyl” or “A” refer to acyclic saturated or unsaturatedhydrocarbon radicals, which may be branched or straight-chain andpreferably have 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, i.e.C₁-C₁₀-alkyls. Examples of suitable alkyl radicals are methyl, ethyl,n-propyl, isopropyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-, 2-or 3-methylbutyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1-or 2-ethylbutyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, 1-, 2-,3- or -methyl-pentyl, n-hexyl, 2-hexyl, isohexyl, n-heptyl, n-octyl,n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tetradecyl, n-hexadecyl,n-octadecyl, n-icosanyl, n-docosanyl.

In a preferred embodiment of the invention, A denotes unbranched orbranched alkyl having 1-10 C atoms, in which 1-7 H atoms may be replacedindependently from one another by Hal. A more preferred A denotesunbranched or branched alkyl having 1-6 C atoms, in which 1-4 atoms maybe replaced independently from one another by Hal. In a most preferredembodiment of the invention, A denotes unbranched or branched alkylhaving 1-4 C atoms, in which 1-3 H atoms can be replaced independentlyfrom one another by Hal. It is highly preferred that A denotesunbranched or branched alkyl having 1-4 C atoms, in which 1-3 H atomscan be replaced independently from one another by F and/or Cl.Particularly preferred is C₁₋₄-alkyl. A C₁₋₄-alkyl radical is forexample a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,sec-butyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl,pentafluoroethyl, 1,1,1-trifluoroethyl or bromomethyl, especiallymethyl, ethyl, propyl or trifluoromethyl. It shall be understood thatthe respective denotation of A is independently of one another in anyradical of the invention.

The terms “carbocycle” or “carbocyclyl” for the purposes of thisinvention refers to a mono- or polycyclic hydrocarbon systems of 3 to 14ring atoms, preferably 4 to 10 ring atoms, more preferably 6 to 8 carbonatoms. The cyclic system may be saturated, mono- or poly-unsaturated, oraromatic.

The term “aryl” or “carboaryl” for the purposes of this invention refersto a mono- or polycyclic aromatic hydrocarbon systems having 3 to 14,preferably 4 to 10, more preferably 6 to 8 carbon atoms, which can beoptionally substituted. The term “aryl” also includes systems in whichthe aromatic cycle is part of a bi- or polycyclic saturated, partiallyunsaturated and/or aromatic system, such as where the aromatic cycle isfused to an aryl, cycloalkyl, heteroaryl or heterocyclyl group asdefined herein via any desired and possible ring member of the arylradical. The bonding to the compounds of the general formula (I) can beeffected via any possible ring member of the aryl radical. Examples ofsuitable aryl radicals are phenyl, biphenyl, naphthyl, 1-naphthyl,2-naphthyl and anthracenyl, but likewise in-danyl, indenyl or1,2,3,4-tetrahydronaphthyl. Preferred carboaryls of the invention areoptionally substituted phenyl, naphthyl and biphenyl, more preferablyoptionally substituted monocylic carboaryl having 6-8 C atoms, mostpreferably optionally substituted phenyl.

In an embodiment of the invention, a carbocycle, including, but notlimited to, carboaryl, is defined as “Ar”. Examples of suitable Arradicals are phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m-or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- orp-tert.-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- orp-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-fluorophenyl, o-,m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-sulfonamidophenyl, o-, m- or p-(N-methyl-sulfonamido)phenyl, o-, m- orp-(N,N-dimethyl-sulfonamido)-phenyl, o-, m- orp-(N-ethyl-N-methyl-sulfonamido)phenyl, o-, m- orp-(N,N-diethyl-sulfonamido)-phenyl, particularly 2,3-, 2,4-, 2,5-, 2,6-,3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl,2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl,2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl,4-fluoro-3-chlorophenyl, 4-chloro-3-fluorophenyl,4-fluoro-3-trifluoromethylphenyl, 4-chloro-3-fluorophenyl,4-chloro-3-trifluoromethylphenyl, 4-chloro-3-methoxylphenyl,3-cyano-4-chloro-phenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl or 2,5-dimethyl-4-chlorophenyl.

Ar preferably denotes an unsaturated or aromatic mono- or bicycliccarbocycle having 3-10 C atoms, which can be substituted by at least onesubstituent selected from the group of Hal, A, OY, CN, COY, COOY, CONYY,NYCOY, NYCONYY, SO₂Y, SO₂NYY, NYSO₂Y, NYY, NO₂, OCN, SCN, SH, optionallysubstituted phenyl and Het¹. In a more preferred embodiment of theinvention, Ar denotes a monocyclic aryl having 4-8 C atoms, which can besubstituted by at least one substituent selected from the group of Hal,A, OY or CN. It is most preferred that Ar denotes phenyl, which can bemono- or disubstituted by at least one substituent selected from thegroup of Hal, A, OA or CN. In a highly preferred embodiment of theinvention, Ar denotes phenyl, which is disubstituted by Hal and A.

The terms “heterocycle” or “heterocyclyl” for the purposes of thisinvention refers to a mono- or polycyclic system of 3 to 14 ring atoms,preferably 4 to 10 ring atoms, more preferably 4 to 8 ring atoms,comprising carbon atoms and 1, 2, 3, 4 or 5 heteroatoms, which areidentical or different, in particular nitrogen, oxygen and/or sulfur.The cyclic system may be saturated, mono- or poly-unsaturated, oraromatic. In the case of a cyclic system consisting of at least tworings the rings may be fused or spiro or otherwise connected. Suchheterocyclyl radicals can be linked via any ring member. The term“heterocyclyl” also includes systems in which the heterocycle is part ofa bi- or polycyclic saturated, partially unsaturated and/or aromaticsystem, such as where the heterocycle is fused to an aryl, cycloalkyl,heteroaryl or heterocyclyl group as defined herein via any desired andpossible ring member of the heterocyclyl radical. The bonding to thecompounds of the general formula (I) can be effected via any possiblering member of the heterocyclyl radical.

Examples of suitable heterocyclyl radicals are pyrrolidinyl,thiapyrrolidinyl, piperidinyl, piperazinyl, oxapiperazinyl,oxapiperidinyl, oxadiazolyl, tetrahydrofuryl, imidazolidinyl,thiazolidinyl, tetrahydropyranyl, morpholinyl, tetrahydrothiophenyl,dihydropyranyl.

The term “heteroaryl” for the purposes of this invention refers to a1-15, preferably 1-9, most preferably 5-, 6- or 7-membered mono- orpolycyclic aromatic hydrocarbon radical which comprises at least 1,where appropriate also 2, 3, 4 or 5 heteroatoms, preferably nitrogen,oxygen and/or sulfur, where the heteroatoms are identical or different.Preferably, the number of nitrogen atoms is 0, 1, 2, 3 or 4, and that ofthe oxygen and sulfur atoms is independently from one another 0 or 1.The term “heteroaryl” also includes systems in which the aromatic cycleis part of a bi- or polycyclic saturated, partially unsaturated and/oraromatic system, such as where the aromatic cycle is fused to an aryl,cycloalkyl, heteroaryl or heterocyclyl group as defined herein via anydesired and possible ring member of the heteroaryl radical. The bondingto the compounds of the general formula (I) can be effected via anypossible ring member of the heteroaryl radical. Examples of suitableheteroaryl are pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl,isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, pyridinyl,pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl,imidazolyl, triazolyl, triazinyl, tetrazolyl, phthalazinyl, indazolyl,indolizinyl, quinoxalinyl, quinazolinyl, pteridinyl, carbazolyl,phenazinyl, phenoxazinyl, phenothiazinyl and acridinyl.

It is preferred that heteroaryl in the realms of “Het¹” denotes anunsaturated or aromatic mono- or bicyclic heterocycle having 2-10 Catoms and 1-4 N, O and/or S atoms, which can be substituted by at leastone substituent selected from the group of Hal, A, OY, CN, COY, COOY,CONYY, NYCOY, NYCONYY, SO₂Y, SO₂NYY, NYSO₂Y, NYY, NO₂, OCN, SCN, SH,optionally substituted phenyl and Het². In a more preferred embodimentof the invention, Het¹ denotes a monocyclic heteroaryl having 4-8 Catoms and 1-3 N atoms, which can be substituted by at least onesubstituent selected from the group of Hal, A or OA. It is mostpreferred that Het¹ denotes pyridyl, which can be mono- or disubstitutedby at least one substituent selected from the group of Hal, A or OA.Highly preferred Het¹ denotes pyridyl, which can be mono- ordisubstituted by at least one substituent selected from the group of Halor A. It shall be understood that the respective denotation of Het¹ isindependently of one another in any radical of the invention.

It is preferred that heteroaryl in the realms of “Het²” denotes anoptionally substituted, saturated, unsaturated or aromatic monocyclic5-6-membered heterocycle having 2-5 C atoms and 1-3 N, O and/or S atoms.In a more preferred embodiment of the invention, Het² denotes asaturated, unsaturated or aromatic monocyclic 5-6-membered heterocyclehaving 2-5 C atoms and 1-2 N, O and/or S atoms.

The term “halogen”, “halogen atom”, “halogen substituent” or “Hal” forthe purposes of this invention refers to one or, where appropriate, aplurality of fluorine (F, fluoro), bromine (Br, bromo), chlorine (Cl,chloro) or iodine (I, iodo) atoms. The designations “dihalogen”,“trihalogen” and “perhalogen” refer respectively to two, three and foursubstituents, where each substituent can be selected independently fromthe group consisting of fluorine, chlorine, bromine and iodine. Halogenpreferably means a fluorine, chlorine or bromine atom. Fluorine andchlorine are more preferred, particularly when the halogens aresubstituted on an alkyl (haloalkyl) or alkoxy group (e.g. CF₃ and CF₃O).It shall be understood that the respective denotation of Hal isindependently of one another in any radical of the invention.

In certain embodiments, the invention provides a compound of formula I,wherein each of W¹, W², W³, W⁴ is independently from one another N or CHbut with the proviso that only one of W¹, W², W³ or W⁴ is N. In otherwords, either W¹, W², W³ or W⁴ is N while the respective three otherradicals are CH. In certain embodiments, W¹ is N, and W², W³, W⁴ are CH.In certain embodiments, W² is N, and W¹, W³, W⁴ are CH.

In certain embodiments, R¹ is Ar. In certain embodiments, R¹ is Het¹.

In certain embodiments, R¹ is phenyl, naphthyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl,[2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl,imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl,3H-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; -1,2,5oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl,phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl,thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl;each of which is optionally substituted.

In various embodiments, R¹ is phenyl or pyridyl, each of which isoptionally substituted.

In various embodiments, R¹ is

In certain embodiments, R² is H. In certain embodiments, R² isunbranched or branched alkyl having 1-10 C atoms, in which 1-7 H atomscan be replaced independently from one another by Hal.

In certain embodiments R³ is H. In certain embodiments, R³ is—(CH₂)_(p)—NR⁴R⁵. In certain embodiments, R³ is —CH₂—NR⁴R⁵.

In certain embodiments, R³ is H,

In certain embodiments, R² and R³ together with the atoms to which eachis attached, forms —(CH₂)_(n)—NH—(CH₂)_(p). In certain embodiments, thegroup is

In certain embodiments, the R⁴, R⁵ radicals according to the presentinvention to be A, or together denote —(CY₂)_(q)—. In certainembodiments, R⁴, R⁵ together denote —(CY₂)_(q)—. In certain embodiments,—(CH₂)_(q)—. In In certain embodiments, R⁴, R⁵ together denote —(CY₂)₃—.

In an aspect of the invention, Y denotes H or A. It shall be understoodthat the respective denotation of Y is independently of one another inany radical of the invention.

In certain embodiments, m is 0 or 1.

In certain embodiments, n is 1 or 2.

In certain embodiments, p is 1 or 2. In certain embodiments, p is 1. Itshall be understood that the respective denotation of p is independentlyof one another in any radical of the invention.

In certain embodiments, q is 3, 4 or 5. In certain embodiments, q is 3or 4. In certain embodiments, q is 3.

Accordingly, the subject-matter of the invention relates to compounds offormula (I), in which at least one of the aforementioned radicals hasany meaning, particularly realize any preferred embodiment, as describedabove. Radicals, which are not explicitly specified in the context ofany embodiment of formula (I), sub-formulae thereof or other radicalsthereto, shall be construed to represent any respective denotationsaccording to formula (I) as disclosed hereunder for solving the problemof the invention. That means that the aforementioned radicals may adoptall designated meanings as each described in the prior or followingcourse of the present specification, irrespective of the context to befound, including, but not limited to, any preferred embodiments. Itshall be particularly understood that any embodiment of a certainradical can be combined with any embodiment of one or more otherradicals.

In certain embodiments, the invention provides a compound of formula(I′):

wherein W¹, W², W³, W⁴, R¹, R², R³ and m are as defined above anddescribed in embodiments, classes and subclasses above and herein,singly or in combination; and/or physiologically acceptable saltsthereof.

In certain embodiments, the invention provides a compound of formula(I″):

wherein W¹, W², W³, W⁴, R¹, R², R³ and m are as defined above anddescribed in embodiments, classes and subclasses above and herein,singly or in combination;and/or physiologically acceptable salts thereof.

In certain embodiments, the invention provides a compound of formula(II):

wherein R¹, R², R³ and m are as defined above and described inembodiments, classes and subclasses above and herein, singly or incombination;and/or physiologically acceptable salts thereof.

In certain embodiments, the invention provides a compound of formula(III):

wherein R¹, R², R³ and m are as defined above and described inembodiments, classes and subclasses above and herein, singly or incombination;and/or physiologically acceptable salts thereof.

In certain embodiments, the invention provides a compound of formula(III-a):

wherein R¹, R², R³ and m are as defined above and described inembodiments, classes and subclasses above and herein, singly or incombination;and/or physiologically acceptable salts thereof.

In certain embodiments, the invention provides a compound of formula(IV):

wherein W¹, W², W³, W⁴, R¹, R³ and n have the meaning as defined aboveand described in embodiments, classes and subclasses above and herein,singly or in combination;and/or physiologically acceptable salts thereof.

In certain embodiments, the invention provides a compound of formula(V):

wherein W¹, W², W³, W⁴, R¹, R³ and n have the meaning as defined aboveand described in embodiments, classes and subclasses above and herein,singly or in combination;and/or physiologically acceptable salts thereof.

In certain embodiments, the invention provides a compound of formula(VI):

wherein W¹, W², W³, W⁴, R¹, R⁴ and R⁵ have the meaning as defined aboveand described in embodiments, classes and subclasses above and herein,singly or in combination;and/or physiologically acceptable salts thereof.

In certain embodiments, the invention provides a compound of formula(VII):

wherein W¹, W², W³, W⁴, R¹, R⁴ and R⁵ have the meaning as defined aboveand described in embodiments, classes and subclasses above and herein,singly or in combination;and/or physiologically acceptable salts thereof.

In certain embodiments, the invention provides a compound of formula(VIII):

wherein R⁴, R⁵ and Ar have the meaning as defined above and described inembodiments, classes and subclasses above and herein, singly or incombination;and/or physiologically acceptable salts thereof.

In certain embodiments, the invention provides a compound of formula(VIII), wherein R⁴ is methyl and R⁵ is H. In certain embodiments, theinvention provides a compound of formula (VIII), wherein R⁴ and R⁵together with the nitrogen, form an azetidine ring.

In certain embodiments, the invention provides a compound of formula(VIII), wherein Ar is phenyl substituted with one or two of halogen orhaloalkyl. In certain embodiments, the invention provides a compound offormula (VIII), wherein Ar is phenyl substituted one or two of Cl orCF₃. In certain embodiments, the invention provides a compound offormula (VIII), wherein Ar is phenyl substituted with one Cl and oneCF₃. In certain embodiments, the invention provides a compound offormula (VIII), wherein Ar is phenyl substituted with two CF₃.

In certain embodiments, the invention provides a compound of formula(VIII), wherein R⁴ is methyl and R⁵ is H. In a further embodiment, Ar isphenyl substituted with one or two of halogen or haloalkyl. In a furtherembodiment, the invention provides a compound of formula (VIII), whereinAr is phenyl substituted with para Cl and meta CF₃.

In certain embodiments, each of W¹, W², W³, W⁴, R¹, R², R³, R⁴ and R⁵and m is as defined above and described in embodiments, classes andsubclasses above and herein, singly or in combination.

In certain embodiments, the invention provides a compound selected from1-76 found in the examples.

The azaquinazoline carboxamide derivatives according to formula (I) andthe starting materials for its preparation, respectively, are producedby methods known per se, as described in the literature (for example instandard works, such as Houben-Weyl, Methoden der organischen Chemie[Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), i.e.under reaction conditions that are known and suitable for saidreactions.

Use can also be made of variants that are known per se, but are notmentioned in greater detail herein. If desired, the starting materialscan also be formed in-situ by leaving them in the un-isolated status inthe crude reaction mixture, but immediately converting them further intothe compound according to the invention. On the other hand, it ispossible to carry out the reaction stepwise.

The reaction is generally carried out in an inert solvent. Suitableinert solvents are, for example, hydrocarbons, such as hexane, petroleumether, benzene, toluene or xylene; chlorinated hydrocarbons, such astrichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroformor dichloromethane; alcohols, such as methanol, ethanol, isopropanol,n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether,diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, suchas ethylene glycol monomethyl or monoethyl ether, ethylene glycoldimethyl ether (diglyme); ketones, such as acetone or butanone; amides,such as acetamide, dimethylacetamide or dimethylformamide (DMF);nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide(DMSO); carbon disulfide; carboxylic acids, such as formic acid, aceticacid or trifluoroacetic acid (TFA); nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents. Particular preference is given to DMF, TFA, H₂O,THF, tert-butanol, tert-amylalcohol, triethylamine or dioxane.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −30° C.and 140° C., normally between −10° C. and 130° C., preferably between 0°C. and 1000.

The present invention also relates to a process for manufacturingcompounds of formula (I) comprising the steps of:

(a) reacting a compound of formula (IX)

-   -   wherein W¹, W², W³ and W⁴ have the meaning as defined above,    -   with a compound of formula (X)

-   -   wherein R¹, R², R³ and m have the meaning as defined above,    -   to yield a compound of formula (I)

-   -   wherein W¹, W², W³, W⁴, R¹, R², R³ and m have the meaning as        defined above,    -   and optionally        (b) converting a base or an acid of the compound of formula (I)        into a salt thereof.

The azaquinazoline carboxamide derivatives of formula (I) are accessiblevia the route above. The starting materials, including the compounds offormulae (IX) and (X) are usually known to the skilled artisan, or theycan be easily prepared by known methods. Accordingly, any compound offormulae (IX) and (X) can be purified, provided as intermediate productand used as starting material for the preparation of compounds offormula (I).

In the final step of the processes above, a salt of the compoundsaccording to formula (I) is optionally provided. The said compoundsaccording to the invention can be used in their final non-salt form. Onthe other hand, the present invention also encompasses the use of thesecompounds in the form of their pharmaceutically acceptable salts, whichcan be derived from various organic and inorganic acids and bases byprocedures known in the art. Pharmaceutically acceptable salt forms ofthe compounds according to the invention are for the most part preparedby conventional methods. If the compound according to the inventioncontains a carboxyl group, one of its suitable salts can be formed bythe reaction of the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline earth metal hydroxides, such as bariumhydroxide and calcium hydroxide; alkali metal alkoxides, for examplepotassium ethoxide and sodium propoxide; and various organic bases, suchas piperidine, diethanolamine and N-methylglutamine. The aluminum saltsof the compounds according to the invention are likewise included. Inmost case of the compounds according to the invention, it is preferredthat acid-addition salts are formed by treating these compounds withpharmaceutically acceptable organic and inorganic acids, for examplehydrogen halides, such as hydrogen chloride, hydrogen bromide orhydrogen iodide, other mineral acids and corresponding salts thereof,such as sulfate, nitrate or phosphate and the like, and alkyl- andmonoarylsulfonates, such as ethanesulfonate, toluenesulfonate andbenzenesulfonate, and other organic acids and corresponding saltsthereof, such as acetate, trifluoroacetate, tartrate, maleate,succinate, citrate, benzoate, salicylate, ascorbate and the like.Accordingly, pharmaceutically acceptable acid-addition salts of thecompounds according to the invention include the following: acetate,adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,camphor-sulfonate, caprylate, chloride, chlorobenzoate, citrate,cyclopentanepropionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate(from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate,glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate,hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate,lactobionate, malate, maleate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, phthalate, but this does not represent a restriction.

With regard to that stated above, it can be seen that the expressions“pharmaceutically acceptable salt” and “physiologically acceptablesalt”, which are used interchangeable herein, in the present connectionare taken to mean an active ingredient which comprises a compoundaccording to the invention in the form of one of its salts, inparticular if this salt form imparts improved pharmacokinetic propertieson the active ingredient compared with the free form of the activeingredient or any other salt form of the active ingredient used earlier.The pharmaceutically acceptable salt form of the active ingredient canalso provide this active ingredient for the first time with a desiredpharmacokinetic property which it did not have earlier and can even havea positive influence on the pharmacodynamics of this active ingredientwith respect to its therapeutic efficacy in the body.

Object of the present invention is also the use of compounds accordingto formula (I) and/or physiologically acceptable salts thereof formodulating and preferably inhibiting p70S6 kinase activity. The term“modulation” denotes any change in p70S6K-mediated signal transduction,which is based on the action of the specific inventive compounds capableto interact with the p70S6K target in such a manner that makesrecognition, binding and inhibition possible. The term “inhibition”denotes any reduction in p70S6K activity, which is based on the actionof the specific inventive compounds capable to interact with the targetp70S6K in such a manner that makes recognition, binding and blockingpossible. The compounds are characterized by such an appreciableaffinity to p70S6K, which ensures a reliable binding and blocking ofp70S6K activity. The same is valid for the Akt target, if appropriate.Preferably, the substances are p70S6K-specific in order to guarantee anexclusive and directed recognition of the p70S6K target. Morepreferably, the substances are bi-specific in order to guarantee anexclusive and directed recognition of the p70S6K target and the Akttarget. In the context of the present invention, the term“recognition”—without being limited thereto—relates to any type ofinteraction between the specific compounds and the target, particularlycovalent or non-covalent binding or association, such as a covalentbond, hydrophobic/hydrophilic interactions, van der Waals forces, ionpairs, hydrogen bonds, ligand-receptor interactions, and the like. Suchassociation may also encompass the presence of other molecules such aspeptides, proteins or nucleotide sequences. The present interaction ischaracterized by high affinity, high selectivity and minimal or evenlacking cross-reactivity to other target molecules to exclude unhealthyand harmful impacts to the treated subject.

A preferred object of the present invention relates to a method forinhibiting p70S6 kinase, wherein a system capable of expressing thep70S6 kinase, preferably expressing the p70S6 kinase, is contacted withat least one compound of formula (I) according to the invention and/orphysiologically acceptable salts thereof, under conditions such thatsaid p70S6 kinase is inhibited. A cellular system is preferred in thescope of the invention. The cellular system is defined to be any subjectprovided that the subject comprises cells. Hence, the cellular systemcan be selected from the group of single cells, cell cultures, tissues,organs and animals. The method for inhibiting p70S6 kinase is preferablyperformed in-vitro. The prior teaching of the present specificationconcerning the compounds of formula (I), including any preferredembodiment thereof, is valid and applicable without restrictions to thecompounds according to formula (I) and their salts when used in themethod for inhibiting p70S6 kinase.

The compounds according to the invention preferably exhibit anadvantageous biological activity, which is easily demonstrated in cellculture-based assays, for example assays as described herein or in priorart. In such assays, the compounds according to the invention preferablyexhibit and cause an inhibiting effect. The compounds of the inventionexhibit EC₅₀ values in the range of 10 nM to 25 μM. It is preferred thatthe compounds of the invention have an activity, as expressed by an EC₅₀standard, of 5 μM or less, preferably 1 μM or less, more preferably 0.5μM or less, most preferably less than 0.1 μM. “EC₅₀” is the effectiveconcentration of a compound that produces 50% of the maximum possibleresponse for that compound.

The method of the invention can be performed either in-vitro or in-vivo.The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be particularly determined by in-vitrotests, whether in the course of research or clinical application.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow the active agents to modulate p70S6K activity,usually between about one hour and one week. In-vitro treatment can becarried out using cultivated cells from a biopsy sample or cell line. Ina preferred aspect of the invention, a follicle cell is stimulated formaturation. The viable cells remaining after the treatment are countedand further processed.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

For identification of a signal transduction pathway and for detection ofinteractions between various signal transduction pathways, variousscientists have developed suitable models or model systems, for examplecell culture models and models of transgenic animals. For thedetermination of certain stages in the signal transduction cascade,interacting compounds can be utilized in order to modulate the signal.The compounds according to the invention can also be used as reagentsfor testing p70S6K-dependent signal transduction pathways in animalsand/or cell culture models or in the clinical diseases mentioned in thisapplication.

The use according to the previous paragraphs of the specification may beeither performed in-vitro or in-vivo models. The modulation can bemonitored by the techniques described in the course of the presentspecification. The in-vitro use is preferably applied to samples ofhumans suffering from hyperproliferative disorders. Testing of severalspecific compounds and/or derivatives thereof makes the selection ofthat active ingredient possible that is best suited for the treatment ofthe human subject. The in-vivo dose rate of the chosen derivative isadvantageously pre-adjusted to the p70S6K susceptibility and/or severityof disease of the respective subject with regard to the in-vitro data.Therefore, the therapeutic efficacy is remarkably enhanced. Moreover,the subsequent teaching of the present specification concerning the useof the compounds according to formula (I) and its derivatives for theproduction of a medicament for the prophylactic or therapeutic treatmentand/or monitoring is considered as valid and applicable withoutrestrictions to the use of the compound for the modulation of p70S6Kactivity if expedient.

As discussed herein, the PI3K signaling pathway is relevant for variousdiseases, preferably in oncology. Accordingly, the compounds accordingto the invention are useful in the prophylaxis and/or treatment ofdiseases that are dependent on the said signaling pathways byinteraction with one or more of the said signaling pathways. The presentinvention therefore relates to compounds according to the invention asmodulators, preferably inhibitors, of the signaling pathways describedherein, preferably of the PI3K-mediated signaling pathway. Inparticular, the invention relates to the use of compounds according tothe invention for the preparation of a medicament for the treatment ofhyperproliferative diseases related to the hyperactivity of p70S6K aswell as diseases modulated by the p70S6K cascade in mammals, ordisorders mediated by aberrant proliferation, such as cancer andinflammation.

The invention furthermore relates to a medicament comprising at leastone compound according to the invention and/or pharmaceutically usablederivatives, salts, solvates and stereoisomers thereof, includingmixtures thereof in all ratios. Preferably, the invention relates to amedicament comprising at least one compound according to the inventionand/or physiologically acceptable salts thereof.

A “medicament” in the meaning of the invention is any agent in the fieldof medicine, which comprises one or more compounds of formula (I) orpreparations thereof (e.g. a pharmaceutical composition orpharmaceutical formulation) and can be used in prophylaxis, therapy,follow-up or aftercare of patients who suffer from diseases, which areassociated with p70S6K activity, in such a way that a pathogenicmodification of their overall condition or of the condition ofparticular regions of the organism could establish at least temporarily.

Consequently, the invention also relates to a pharmaceutical compositioncomprising as active ingredient at least one compound of formula (I)according to the invention and/or physiologically acceptable saltsthereof together with pharmaceutically tolerable adjuvants and/orexcipients. It shall be understood that the compound of the invention isprovided in an effective amount.

In the meaning of the invention, an “adjuvant” denotes every substancethat enables, intensifies or modifies a specific response against theactive ingredient of the invention if administered simultaneously,contemporarily or sequentially. Known adjuvants for injection solutionsare, for example, aluminum compositions, such as aluminum hydroxide oraluminum phosphate, saponins, such as QS21, muramyldipeptide ormuramyltripeptide, proteins, such as gamma-interferon or TNF, M59,squalen or polyols.

Furthermore, the active ingredient may be administered alone or incombination with other treatments. A synergistic effect may be achievedby using more than one compound in the pharmaceutical composition, i.e.the compound of formula (I) is combined with at least another agent asactive ingredient, which is either another compound of formula (I) or acompound of different structural scaffold. The active ingredients can beused either simultaneously or sequentially. The invention also relatesto a compound or pharmaceutical composition for inhibiting abnormal cellgrowth/cancer in a mammal which comprises an amount of a compound of thepresent invention, or a pharmaceutically acceptable salt or solvate orprodrug thereof, in combination with an amount of another anti-cancertherapeutic, wherein the amounts of the compound, salt, solvate, orprodrug, and of the chemotherapeutic are together effective ininhibiting abnormal cell growth/cancer. The present compounds aresuitable for combination with known anti-cancer agents.

Many oncology therapeutics are presently known in the art. In apreferred embodiment, the other active pharmaceutical ingredient is ananti-cancer therapeutic that is a chemotherapeutic selected from thegroup consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, anti-hormones, angiogenesis inhibitors, andanti-androgens. In another preferred embodiment of the invention, theanti-cancer therapeutic is an antibody selected from the groupconsisting of bevacizumab, CD40-specific antibodies, chTNT-1/B,denosumab, zanolimumab, IGF1R-specific antibodies, lintuzumab,edrecolomab, WX G250, rituximab, ticilimumab, trastuzumab and cetuximab.In yet another preferred embodiment of the invention, the anti-cancertherapeutic is an inhibitor of another protein kinase, such as Akt, Axl,dyrk2, epha2, fgfr3, igf1r, IKK2, JNK3, Vegfr1, Vegfr2, Vegfr3 (alsoknown as Flt-4), KDR, MEK, MET, Plk1, RSK1, Src, TrkA, Zap70, cKit,bRaf, EGFR, Jak2, PI3K, NPM-Alk, c-Abl, BTK, FAK, PDGFR, TAK1, LimK,Flt-3, PDK1, and Erk. Further anti-cancer agents are known to those ofskill in the art and are useful with the compounds of the presentinvention.

The invention also relates to a set (kit) consisting of separate packsof an effective amount of a compound according to the invention and/orpharmaceutically acceptable salts, derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient. The setcomprises suitable containers, such as boxes, individual bottles, bagsor ampoules. The set may, for example, comprise separate ampoules, eachcontaining an effective amount of a compound according to the inventionand/or pharmaceutically acceptable salts, derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient in dissolvedor lyophilized form.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

The pharmaceutical composition of the invention is produced in a knownway using common solid or liquid carriers, diluents and/or additives andusual adjuvants for pharmaceutical engineering and with an appropriatedosage. The amount of excipient material that is combined with theactive ingredient to produce a single dosage form varies depending uponthe host treated and the particular mode of administration. Suitableexcipients include organic or inorganic substances that are suitable forthe different routes of administration, such as enteral (e.g. oral),parenteral or topical application, and which do not react with compoundsof formula (I) or salts thereof. Examples of suitable excipients arewater, vegetable oils, benzyl alcohols, alkylene glycols, polyethyleneglycols, glycerol triacetate, gelatin, carbohydrates, e.g. lactose orstarch, magnesium stearate, talc and petroleum jelly.

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multi-dose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilized) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary. Injectionsolutions and suspensions prepared in accordance with the recipe can beprepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavors.

In a preferred embodiment of the present invention, the pharmaceuticalcomposition is adapted for oral administration. The preparations can besterilized and/or can comprise auxiliaries, such as carrier proteins(e.g. serum albumin), lubricants, preservatives, stabilizers, fillers,chelating agents, antioxidants, solvents, bonding agents, suspendingagents, wetting agents, emulsifiers, salts (for influencing the osmoticpressure), buffer substances, colorants, flavorings and one or morefurther active substances, for example one or more vitamins. Additivesare well known in the art, and they are used in a variety offormulations.

Accordingly, the invention also relates to a pharmaceutical compositioncomprising as active pharmaceutical ingredient at least one compound offormula (I) according to the invention and/or physiologically acceptablesalts thereof together with pharmaceutically tolerable adjuvants,optionally in combination with at least another active pharmaceuticalingredient. Both active pharmaceutical ingredients are particularlyprovided in effective amounts. The prior teaching of the presentspecification concerning administration route and combination product,respectively, is valid and applicable without restrictions to thecombination of both features if expedient.

The terms “effective amount” or “effective dose” or “dose” areinterchangeably used herein and denote an amount of the pharmaceuticalcompound having a prophylactically or therapeutically relevant effect ona disease or pathological conditions, i.e. which causes in a tissue,system, animal or human a biological or medical response which is soughtor desired, for example, by a researcher or physician. A “prophylacticeffect” reduces the likelihood of developing a disease or even preventsthe onset of a disease. A “therapeutically relevant effect” relieves tosome extent one or more symptoms of a disease or returns to normalityeither partially or completely one or more physiological or biochemicalparameters associated with or causative of the disease or pathologicalconditions. In addition, the expression “therapeutically effectiveamount” denotes an amount which, compared with a corresponding subjectwho has not received this amount, has the following consequence:improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side-effects or also thereduction in the advance of a disease, complaint or disorder. Theexpression “therapeutically effective amount” also encompasses theamounts which are effective for increasing normal physiologicalfunction.

The respective dose or dosage range for administering the pharmaceuticalcomposition according to the invention is sufficiently high in order toachieve the desired prophylactic or therapeutic effect of reducingsymptoms of the aforementioned diseases, such as cancer andinflammation. It will be understood that the specific dose level,frequency and period of administration to any particular human willdepend upon a variety of factors including the activity of the specificcompound employed, the age, body weight, general state of health,gender, diet, time and route of administration, rate of excretion, drugcombination and the severity of the particular disease to which thespecific therapy is applied. Using well-known means and methods, theexact dose can be determined by one of skill in the art as a matter ofroutine experimentation. The prior teaching of the present specificationis valid and applicable without restrictions to the pharmaceuticalcomposition comprising the compounds of formula (I) if expedient.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. The concentration of the prophylactically ortherapeutically active ingredient in the formulation may vary from about0.1 to 100 wt %. Preferably, the compound of formula (I) or thepharmaceutically acceptable salts thereof are administered in doses ofapproximately 0.5 to 1000 mg, more preferably between 1 and 700 mg, mostpreferably 5 and 100 mg per dose unit. Generally, such a dose range isappropriate for total daily incorporation. In other terms, the dailydose is preferably between approximately 0.02 and 100 mg/kg of bodyweight. The specific dose for each patient depends, however, on a widevariety of factors as already described in the present specification(e.g. depending on the condition treated, the method of administrationand the age, weight and condition of the patient). Preferred dosage unitformulations are those which comprise a daily dose or part-dose, asindicated above, or a corresponding fraction thereof of an activeingredient. Furthermore, pharmaceutical formulations of this type can beprepared using a process which is generally known in the pharmaceuticalart.

Although a therapeutically effective amount of a compound according tothe invention has to be ultimately determined by the treating doctor orvet by considering a number of factors (e.g. the age and weight of theanimal, the precise condition that requires treatment, severity ofcondition, the nature of the formulation and the method ofadministration), an effective amount of a compound according to theinvention for the treatment of neoplastic growth, for example colon orbreast carcinoma, is generally in the range from 0.1 to 100 mg/kg ofbody weight of the recipient (mammal) per day and particularly typicallyin the range from 1 to 10 mg/kg of body weight per day. Thus, the actualamount per day for an adult mammal weighing 70 kg is usually between 70and 700 mg, where this amount can be administered as a single dose perday or usually in a series of part-doses (such as, for example, two,three, four, five or six) per day, so that the total daily dose is thesame. An effective amount of a salt or solvate or of a physiologicallyfunctional derivative thereof can be determined as the fraction of theeffective amount of the compound according to the invention per se. Itcan be assumed that similar doses are suitable for the treatment ofother conditions mentioned above.

The pharmaceutical composition of the invention can be employed asmedicament in human and veterinary medicine. According to the invention,the compounds of formula (I) and/or physiologically salts thereof aresuited for the prophylactic or therapeutic treatment and/or monitoringof diseases that are caused, mediated and/or propagated by p70S6Kactivity. It is preferred that the diseases are selected from the groupof hyperproliferative disorders, cancer, metastases, tumors,angiogenesis disorders, tumor angiogenesis, benign hyperplasia,hemangioma, glioma, melanoma, Kaposi's sarcoma, prostate diseasesrelated to vasculogenesis or angiogenesis, inflammation, pancreatitis,retinopathy, retinopathy of prematurity, diabetic retinopathy, diabetes,pain, restenosis, psoriasis, eczema, scleroderma and age-related maculardegeneration. It shall be understood that the host of the compound isincluded in the present scope of protection according to the presentinvention.

Particular preference is given to the treatment of cancer, such asbrain, lung, colon, epidermoid, squamous cell, bladder, gastric,pancreatic, breast, head, neck, renal, kidney, liver, ovarian, prostate,colorectal, uterine, rectal, oesophageal, testicular, gynecological,thyroid cancer, melanoma; hematologic malignancies, such as acutemyelogenous leukemia, multiple myeloma, chronic myelogneous leukemia,myeloid cell leukemia; glioma; Kaposi's sarcoma; or any other type ofsolid or liquid tumors. More preferably, the cancer to be treated ischosen from breast, colorectal, lung, prostate or pancreatic cancer, orglioblastoma.

Exemplary disorders treated by the compounds of the invention includeprostate cancer, thyroid cancer, liver cancer, lung cancer, breastcancer, colon cancer, prostate cancer, pituitary tumors, carcinoma ofthe bladder, breast, colon (e.g. colorectal carcinomas such as colonadenocarcinoma and colon adenoma), kidney, epidermis, liver, lung, forexample adenocarcinoma, small cell lung cancer and non-small cell lungcarcinomas, oesophagus, gall bladder, ovary, pancreas e.g. exocrinepancreatic carcinoma, stomach, cervix, endometrium, thyroid, prostate,or skin, for example squamous cell carcinoma; a hematopoietic tumour oflymphoid lineage, for example leukemia, acute lymphocytic leukemia,chronic lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma,Hodgkin's lymphoma, non-Hodgkin's lymphoma; hairy cell lymphoma, orBurkett's lymphoma; a hematopoietic tumour of myeloid lineage, forexample leukemias, acute and chronic myelogenous leukemias,myeloproliferative syndrome, myelodysplastic syndrome, or promyelocyticleukemia; multiple myeloma; thyroid follicular cancer; a tumour ofmesenchymal origin, for example fibrosarcoma or rhabdomyosarcoma; atumour of the central or peripheral nervous system, for exampleastrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma;teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoctanthoma;thyroid follicular cancer; or Kaposi's sarcoma.

In certain embodiments, the disorder is bladder cancer, breast cancer,cervical cancer, colon cancer, epidermis cancer, gall bladder cancer,kidney cancer, liver cancer, lung cancer, pituitary tumors, oesophaguscancer, ovarian cancer, pancreatic cancer, prostate cancer, stomachcancer, thyroid cancer, leukemia, B-cell lymphoma, T-cell lymphoma,Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma,Burkett's lymphoma, acute and chronic myelogenous leukemias,myeloproliferative syndrome, myelodysplastic syndrome, promyelocyticleukemia; multiple myeloma, thyroid follicular cancer; astrocytoma,neuroblastoma, glioma, schwannoma, melanoma or Kaposi's sarcoma.

In certain embodiments, the disorder is multiple myeloma,myeloproliferatoive disorders, endometrial cancer, prostate cancer,bladder cancer, lung cancer, ovarian cancer, breast cancer, gastriccancer, colorectal cancer, and oral squamous cell carcinoma. In certainembodiments, the disorder is multiple myeloma, bladder cancer, cervicalcancer, prostate cancer, thyroid carcinomas, lung cancer, breast cancer,or colon cancer.

Further preference is given to treatment of a disease related tovasculogenesis or angiogenesis in a mammal, which comprises theadministration of a therapeutically effective amount of a compound ofthe present invention, or a pharmaceutically acceptable salt, prodrug orhydrate thereof, and a pharmaceutically acceptable carrier. In oneembodiment, the compound or pharmaceutical composition of the inventionis for treating a disease selected from the group consisting of tumorangiogenesis; chronic inflammatory disease, such as rheumatoidarthritis, inflammatory bowel disease, atherosclerosis; skin diseases,such as psoriasis, eczema, scleroderma; metabolic diseases, such asdiabetes, obesity, metabolic syndrome, insulin resistance,hyperglycemia, hyperaminoacidemia, hyperlipidmia, diabetic retinopathy,retinopathy of prematurity; and age-related macular degeneration.

The invention also relates to the use of compounds according to formula(I) and/or physiologically acceptable salts thereof for the prophylacticor therapeutic treatment and/or monitoring of diseases that are caused,mediated and/or propagated by p70S6 activity.

Furthermore, the invention relates to the use of compounds according toformula (I) and/or physiologically acceptable salts thereof for theproduction of a medicament for the prophylactic or therapeutic treatmentand/or monitoring of diseases that are caused, mediated and/orpropagated by p70S6K activity. Compounds of formula (I) and/or aphysiologically acceptable salt thereof can furthermore be employed asintermediate for the preparation of further medicament activeingredients. The medicament is preferably prepared in a non-chemicalmanner, e.g. by combining the active ingredient with at least one solid,fluid and/or semi-fluid carrier or excipient, and optionally inconjunction with a single or more other active substances in anappropriate dosage form.

Another object of the present invention are compounds of formula (I)according to the invention and/or physiologically acceptable saltsthereof for use in the prophylactic or therapeutic treatment and/ormonitoring of diseases that are caused, mediated and/or propagated byp70S6K activity. Another preferred object of the invention concernscompounds of formula (I) according to the invention and/orphysiologically acceptable salts thereof for use in the prophylactic ortherapeutic treatment and/or monitoring of hyperproliferative disorders.The prior teaching of the present specification concerning the compoundsof formula (I), including any preferred embodiment thereof, is valid andapplicable without restrictions to the compounds according to formula(I) and their salts for use in the prophylactic or therapeutic treatmentand/or monitoring of hyperproliferative disorders.

The compounds of formula (I) according to the invention can beadministered before or following an onset of disease once or severaltimes acting as therapy. The aforementioned compounds and medicalproducts of the inventive use are particularly used for the therapeutictreatment. A therapeutically relevant effect relieves to some extent oneor more symptoms of a disorder, or returns to normality, eitherpartially or completely, one or more physiological or biochemicalparameters associated with or causative of a disease or pathologicalcondition. Monitoring is considered as a kind of treatment provided thatthe compounds are administered in distinct intervals, e.g. in order tobooster the response and eradicate the pathogens and/or symptoms of thedisease completely. Either the identical compound or different compoundscan be applied. The medicament can also be used to reducing thelikelihood of developing a disorder or even prevent the initiation ofdisorders associated with p70S6K activity in advance or to treat thearising and continuing symptoms. The disorders as concerned by theinvention are preferably hyperproliferative disorders.

In the meaning of the invention, prophylactic treatment is advisable ifthe subject possesses any preconditions for the aforementionedphysiological or pathological conditions, such as a familialdisposition, a genetic defect, or a previously passed disease.

It is another object of the invention to provide a method for treatingdiseases that are caused, mediated and/or propagated by p70S6K activity,wherein at least one compound of formula (I) according to the inventionand/or physiologically acceptable salts thereof is administered to amammal in need of such treatment. It is another preferred object of theinvention to provide a method for treating hyperproliferative disorders,wherein at least one compound of formula (I) according to the inventionand/or physiologically acceptable salts thereof is administered to amammal in need of such treatment. The compound is preferably provided inan effective amount as defined above. The preferred treatment is an oraladministration.

In another preferred aspect, the method for treating cancer in a mammalcomprises administering to the mammal an amount of a compound of thepresent invention in combination with radiation therapy, wherein theamount of the compound is in combination with the radiation therapyeffective in treating cancer in the mammal. Techniques for administeringradiation therapy are known in the art, and these techniques can be usedin the combination therapy described herein. The amount andadministration of a compound of the invention in this combinationtherapy can be determined according to the means for ascertainingeffective amounts, doses and routes of such compounds as describedherein. It is believed that the compounds of the present invention canrender abnormal cells more sensitive to treatment with radiation forpurposes of killing and/or inhibiting the growth of such cells.Accordingly, this invention relates to a method for sensitizing abnormalcells in a mammal to treatment with radiation which comprisesadministering to the mammal an amount of a compound of the presentinvention which amount is effective in sensitizing abnormal cells totreatment with radiation.

It is still another aspect of the invention to provide a method forinhibiting abnormal cell growth in a mammal which comprises an amount ofa compound of the present invention or an isotopically-labeledderivative thereof, and an amount of one or more substances selectedfrom anti-angiogenesis agents, signal transduction inhibitors, andanti-proliferative agents.

The disclosed compounds of the formula I can be administered incombination with other known therapeutic agents, including anticanceragents. As used here, the term “anticancer agent” relates to any agentwhich is administered to a patient with cancer for the purposes oftreating the cancer.

The anti-cancer treatment defined above may be applied as a monotherapyor may involve, in addition to the herein disclosed compounds of formulaI, conventional surgery or radiotherapy or medicinal therapy. Suchmedicinal therapy, e.g. a chemotherapy or a targeted therapy, mayinclude one or more, but preferably one, of the following anti-tumoragents:

Alkylating agents: such as altretamine, bendamustine, busulfan,carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine,ifosfamide, improsulfan, tosilate, lomustine, melphalan, mitobronitol,mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan,mechloretamine, carboquone; apaziquone, fotemustine, glufosfamide,palifosfamide, pipobroman, trofosfamide, uramustine, TH-302⁴, VAL-083⁴;Platinum Compounds: such as carboplatin, cisplatin, eptaplatin,miriplatine hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin,satraplatin; lobaplatin, nedaplatin, picoplatin, satraplatin;DNA altering agents: such as amrubicin, bisantrene, decitabine,mitoxantrone, procarbazine, trabectedin, clofarabine; amsacrine,brostallicin, pixantrone, laromustine^(1,3);Topoisomerase Inhibitors: such as etoposide, irinotecan, razoxane,sobuzoxane, teniposide, topotecan; amonafide, belotecan, elliptiniumacetate, voreloxin;Microtubule modifiers: such as cabazitaxel, docetaxel, eribulin,ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine,vindesine, vinflunine; fosbretabulin, tesetaxel;Antimetabolites: such as asparaginase³, azacitidine, calciumlevofolinate, capecitabine, cladribine, cytarabine, enocitabine,floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine,methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine,thioguanine, carmofur; doxifluridine, elacytarabine, raltitrexed,sapacitabine, tegafur^(2,3), trimetrexate;Anticancer antibiotics: such as bleomycin, dactinomycin, doxorubicin,epirubicin, idarubicin, levamisole, miltefosine, mitomycin C,romidepsin, streptozocin, valrubicin, zinostatin, zorubicin,daunurobicin, plicamycin; aclarubicin, peplomycin, pirarubicin;Hormones/Antagonists: such as abarelix, abiraterone, bicalutamide,buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone,estradiol, fluocortolone fluoxymesterone, flutamide, fulvestrant,goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin,nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen,thyrotropin alfa, toremifene, trilostane, triptorelin,diethylstilbestrol; acolbifene, danazol, deslorelin, epitiostanol,orteronel, enzalutamide^(1,3);Aromatase inhibitors: such as aminoglutethimide, anastrozole,exemestane, fadrozole, letrozole, testolactone; formestane;Small molecule kinase inhibitors: such as crizotinib, dasatinib,erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib,ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib,gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib,dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib,linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib,perifosine, ponatinib, radotinib, rigosertib, tipifarnib, tivantinib,tivozanib, trametinib, pimasertib, brivanib alaninate, cediranib,apatinib⁴, cabozantinib S-malate^(1,3), ibrutinib^(1,3), icotinib⁴,buparlisib², cipatinib⁴, cobimetinib^(1,3), idelalisib^(1,3),fedratinib¹, XL-647⁴;Photosensitizers: such as methoxsalen³; porfimer sodium, talaporfin,temoporfin;Antibodies: such as alemtuzumab, besilesomab, brentuximab vedotin,cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab,tositumomab, trastuzumab, bevacizumab, pertuzumab^(2,3); catumaxomab,elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab,nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab, ramucirumab,rilotumumab, siltuximab, tocilizumab, zalutumumab, zanolimumab,matuzumab, dalotuzumab^(1,2,3), onartuzumab^(1,3), racotumomab¹,tabalumab^(1,3), EMD-525797⁴, nivolumab^(1,3);Cytokines: such as aldesleukin, interferon alfa², interferon alfa2a³,interferon alfa2b^(2,3); celmoleukin, tasonermin, teceleukin,oprelvekin^(1,3), recombinant interferon beta-1a⁴;Drug Conjugates: such as denileukin diftitox, ibritumomab tiuxetan,iobenguane I123, prednimustine, trastuzumab emtansine, estramustine,gemtuzumab, ozogamicin, aflibercept; cintredekin besudotox, edotreotide,inotuzumab ozogamicin, naptumomab estafenatox, oportuzumab monatox,technetium (99mTc) arcitumomab^(1,3), vintafolide^(1,3);Vaccines: such as sipuleucel³; vitespen³, emepepimut-S³, oncoVAX⁴,rindopepimut³, troVax⁴, MGN-1601⁴, MGN-1703⁴; andMiscellaneous: alitretinoin, bexarotene, bortezomib, everolimus,ibandronic acid, imiquimod, lenalidomide, lentinan, metirosine,mifamurtide, pamidronic acid, pegaspargase, pentostatin, sipuleucel³,sizofiran, tamibarotene, temsirolimus, thalidomide, tretinoin,vismodegib, zoledronic acid, vorinostat; celecoxib, cilengitide,entinostat, etanidazole, ganetespib, idronoxil, iniparib, ixazomib,lonidamine, nimorazole, panobinostat, peretinoin, plitidepsin,pomalidomide, procodazol, ridaforolimus, tasquinimod, telotristat,thymalfasin, tirapazamine, tosedostat, trabedersen, ubenimex, valspodar,gendicine⁴, picibanil⁴, reolysin⁴, retaspimycin hydrochloride^(1,3),trebananib^(2,3), virulizin⁴, carfilzomib^(1,3), endostatin⁴,immucothel⁴, belinostat³, MGN-1703⁴. (¹ Prop. INN (ProposedInternational Nonproprietary Name); ² Rec. INN (RecommendedInternational Nonproprietary Names); ³ USAN (United States AdoptedName); ⁴ no INN).

The above teaching of the invention and its embodiments is valid andapplicable without restrictions to the methods of treatment ifexpedient.

In the scope of the present invention, novel azaquinazoline carboxamidecompounds of formula (I) are provided for the first time. The p70S6Kinhibitors of the invention are structurally distinct from compounds inthe art because of introducing heteroatoms into the quinazolinecarboxamide scaffold. The invention comprises the use of compounds offormula (I) in the regulation, modulation and/or inhibition of the PI3Ksignal cascade via p70S6K, which a member of said pathway. The compoundsof the invention can be advantageously applied as research tool, fordiagnosis and/or in treatment of any disorders that are responsive top70S6K signaling and inhibition.

For example, the compounds of the invention are useful in-vitro asunique tools for understanding the biological role of p70S6K, includingthe evaluation of the many factors thought to influence, and beinfluenced by, the production of p70S6K. The present compounds are alsouseful in the development of other compounds that interact with p70S6Ksince the present compounds provide important structure-activityrelationship (SAR) information that facilitate that development.

The compounds of the invention are potent, selective and orallybioavailable p70S6K inhibitors that address this unmet medical need forthe several conditions, particularly cancer and inflammation, withrespect to the progressive features of the diseases. Medicaments andpharmaceutical compositions containing said compounds and the use ofsaid compounds to treat p70S6K-mediated conditions is a promising, novelapproach for a broad spectrum of therapies causing a direct andimmediate improvement in the state of health, whether in man and animal.The impact is of special benefit to efficiently combathyperproliferative disorders, either alone or in combination with othertreatments.

Due to the surprisingly appreciable inhibitory activity on p70S6K, thecompounds of the invention can be advantageously administered at lowerdoses compared to other less potent or selective inhibitors of prior artwhile still achieving equivalent or even superior desired biologicaleffects. In addition, such a dose reduction advantageously leads to lessor even no medicinal adverse effects. Moreover, the compounds of formula(I), their salts, isomers, tautomers, enantiomeric forms, diastereomers,racemates, derivatives, prodrugs and/or metabolites are characterized bya high specificity and stability, low manufacturing costs and convenienthandling. These features form the basis for a reproducible action,wherein the lack of cross-reactivity is included, and for a reliable andsafe interaction with the target structure.

All the references cited herein are incorporated by reference in thedisclosure of the invention hereby.

It is to be understood that this invention is not limited to theparticular compounds, pharmaceutical compositions, uses and methodsdescribed herein, as such matter can, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only and is not intended to limit thescope of the present invention, which is only defined by the appendedclaims. As used herein, including the appended claims, singular forms ofwords such as “a,” “an,” and “the” include their corresponding pluralreferents unless the context clearly dictates otherwise. Thus, e.g.,reference to “a compound” includes a single or several differentcompounds, and reference to “a method” includes reference to equivalentsteps and methods known to a person of ordinary skill in the art, and soforth. Unless otherwise defined, all technical and scientific terms usedherein have the same meaning as commonly understood by a person ofordinary skill in the art to which this invention belongs.

The techniques that are essential according to the invention aredescribed in detail in the specification. Other techniques which are notdescribed in detail correspond to known standard methods that are wellknown to a person skilled in the art, or the techniques are described inmore detail in cited references, patent applications or standardliterature. Although methods and materials similar or equivalent tothose described herein can be used in the practice or testing of thepresent invention, suitable examples are described below. The followingexamples are provided by way of illustration and not by way oflimitation. Within the examples, standard reagents and buffers that arefree from contaminating activities (whenever practical) are used. Theexample are particularly to be construed such that they are not limitedto the explicitly demonstrated combinations of features, but theexemplified features may be unrestrictedly combined again if thetechnical problem of the invention is solved. Similarly, the features ofany claim can be combined with the features of one or more other claims.

In the following examples, “conventional workup” means: water was addedif necessary, the pH was adjusted, if necessary, to a value of between 2and 10, depending on the constitution of the end product, the mixturewas extracted with ethyl acetate or dichloromethane, the phases wereseparated, the organic phase was dried over sodium sulfate andevaporated, and the product was purified by chromatography on silica gelor C-18, and/or by crystallization.

Some abbreviations that may appear in this application are as follows:

ACN acetonitrile AcOH Acetic acid AIBN Azobisisobutylonitrile ATPAdenosine triphosphate b Broad peak Bop-ClBis(2-oxo-3-oxazolidinyl)phosphinic chloride Conc. concentrated dDoublet DCM Dichloromethane DCE dichloroethane DMAPdimethylaminopyridine DMF dimethylformamide DMSO dimethylsulfoxideDIEA/DIPEA N,N-Diisopropylethylamine DTT dithiothreitol EDTAEthylenediaminetetraacetic acid equiv./eq. equivalents Et ethyl h hourHEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HPLC Highpressure liquid chromatography LC/MS Liquid chromatography coupled tomass spectrometry LiOH Lithium hydroxide m multiplet M Molecular ion m/zMass-to-charge ratio Me methyl MeOH methanol min minute MS Massspectrometry N Normal (unit of concentration) NaOH Sodium hydroxide NBSN-bromosuccinimide NMO 4-methylmorpholine N-oxide NMPN-Methyl-2-pyrrolidone NMR Nuclear Magnetic Resonance PG Protectinggroup psi Pounds per square inch PyBOP(Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate qQuartette (or quartet) Rf Retention factor RT/rt Room temperature Rt.Retention time s Singlet T3P Propylphosphonic anhydride TBAFTetrabutylammonium fluoride Tert Tertiary TEA Triethylamine TFATrifluoroacetic acid THAB Tetrahexylammonium bromide THF TetrahydrofuranUV ultraviolet VIS visibleNMR Spectra

NMR Spectra were acquired on a Varian ^(Unity)Inova or Bruker 400 MHzNMR spectrometer equipped with an Automation Triple Broadband (ATB)probe. The ATB probe was simultaneously tuned to ¹H, ¹⁹F and ¹³C. Fortypical ¹H NMR spectra, the pulse angle was 45 degrees, 8 scans weresummed and the spectral width was 16 ppm (−2 ppm to 14 ppm). A total of32768 complex points were collected during the 5.1 second acquisitiontime, and the recycle delay was set to 1 second. Spectra were collectedat 25° C. ¹H NMR Spectra are typically processed with 0.2 Hz linebroadening and zero-filling to 131072 points prior to Fouriertransformation.

Analytical LC/MS was performed using the following three methods:

Method A: A Discovery C¹⁸, 5 μm, 3×30 mm column was used at a flow rateof 400 μL/min, sample loop 5 μL, mobile phase: (A) water with 0.1%formic acid, mobile phase, (B) methanol with 0.1% formic acid; retentiontimes are given in minutes. Method details: (I) runs on a QuaternaryPump G1311A (Agilent) with UV/VIS diode array detector G1315B (Agilent)and Finnigan LCQ Duo MS detector in ESI+ modus with UV-detection at 254and 280 nm with a gradient of 15-95% (B) in a 3.2 min linear gradient;(11) hold for 1.4 min at 95% (B); (111) decrease from 95-15% (B) in a0.1 min linear gradient; (IV) hold for 2.3 min at 15% (B).Method B: A Waters Symmetry C¹⁸, 3.5 μm, 4.6×75 mm column at a flow rateof 1 mL/min, sample loop 10 μL, mobile phase (A) is water with 0.05%TFA, mobile phase (B) is ACN with 0.05% TFA; retention times are givenin minutes. Methods details: (I) runs on a Binary Pump G1312A (Agilent)with UV/Vis diode array detector G1315B (Agilent) and Agilent G1956B(SL) MS detector in ESI+ mode with UV-detection at 254 and 280 nm with agradient of 20-85% (B) in a 10 min linear gradient; (II) hold for 1 minat 85% (B); (Ill) decrease from 20-85% (B) in a 0.2 min linear gradient;(IV) hold for 3.8 min at 20% (B).Method C: Gradient: 4.2 min; Flow: 2 ml/min; 99:1-0:100 Water+0.1%(Vol.) TFA, Acetonitril+0.1% (Vol.) TFA; (i) 0.0 to 0.2 min: 99:1; (ii)0.2 to 3.8 min: 99:1→0:100; (iii) 3.8 to 4.2 min: 0:100; Column:Chromolith Performance RP18e; 100 mm long, 3 mm diameter; Wavelength:220 nm.Analytical Chiral HPLC

Analytical chiral HPLC was performed using a ChiralPak AD-H column(250×4.6 mm) from Daicel Chemical Industries, Ltd. on an Agilent 1100Series system. The method used a 5.0 μL injection volume, with a flowrate of 1 mL/min of 100% methanol for 15 min at 25° C., and UV-detectionat 254 and 280 nm.

Preparative HPLC

Preparative HPLC was performed using either a Waters Atlantis dC₁₈ OBD10 μM (30×250 mm) column or a Waters Sunfire Prep C₁₈ OBD 10 μM (30×250mm) column. The columns were used at a flow rate of 60 mL/min on aWaters Prep LC 4000 System equipped with a sample loop (10 mL) and anISCO UA-6 UV/Vis detector. The mobile phase was drawn from two solventreservoirs containing (A) water and (B) HPLC-grade acetonitrile. Atypical preparative run used a linear gradient (e.g., 0-60% solvent Bover 60 min).

The present invention also relates to processes for manufacturing thecompounds according to the hereinafter described schemes and workingexamples.

General Synthetic Schemes

Example 1: Synthesis of Intermediates

Amino Phenylethanamine Dihydrochloride (B) (Scheme 1A)

A solution of alcohol intermediate A (3.17 mmol) in DCM (5.00 mL) wascooled to −78° C. and treated with triethylamine (9.52 mmol) andmethanesulfonyl chloride (4.76 mmol) then stirred for 30-60 minutesbefore being quenched with saturated sodium bicarbonate solution (10mL). The organic layer was extracted with brine, dried over magnesiumsulfate, filtered and concentrated to give the corresponding mesylatewhich was used without further purification.

The mesylate was treated with amine (2-5 eq. if neat; or 1.5 eq. if inTHF solution) at room temperature for 30-60 minutes. The resultantdesired 2-phenylethan-1,2-diamine was diluted with EtOAc and subjectedto aqueous extraction with saturated sodium bicarbonate. The organiclayers were washed with brine, dried over magnesium sulfate, filteredand concentrated. The crude residue was then purified under normal phasechromatography (20-50% EtOAc in hexanes on silica gel) to afford thepure desired boc-protected amino phenylethanamine intermediate as awhite solid in yield of (55-78%).

A suspension of the Boc-protected amino phenylethanamine intermediate(0.22 mmol) in anhydrous DCM (2 mL) was treated with 4.0 M HCl in1,4-dioxane (1.1 mmol, 5 eq), and the contents were stirred at roomtemperature. Dissolution occurred, followed by precipitation of a solid.After 3 hours, the solid was collected by filtration, washed withdiethyl ether (10 mL) and dried under vacuum for 2 hours to afford B asa white or off-white solid (63-95%).

Amino Phenylethanamine Dihydrochloride (B) (Scheme 1B)

A suspension of the cyclic sulfone intermediate C (52.52 mmol) in CH₃CN(100 mL) was treated with a secondary amine (65.67 mmol, 1.25 eq), andthe contents were stirred at room temp for 30-60 minutes. A solidprecipitated, which was filtered, washed with MeOH or acetone (100 mL)and dried under vacuum for 2 hours to provide the Boc-protected aminophenylethanamine intermediate (60-77%) as a white solid.

A suspension of the Boc-protected amino phenylethanamine intermediate(38.61 mmol) in anhydrous MeOH (50 mL) was treated with 2.0 M HCl indiethyl ether (200 mmol, 5 eq), and the contents were stirred at roomtemperature. Dissolution occurred, followed by precipitation of a solid.After 3 hours, the solid was collected by filtration, washed withdiethyl ether (100 mL) and dried under vacuum for 2 hours to afford B asa white or off-white solid (69-75%).

Amino Phenylethanamine Dihydrochloride (D) (Scheme 2)

N-alkyl-4-nitrobenzenesulfonamide (7.84 mmol) was added to a suspensionof powdered potassium hydroxide (15.68 mmol) in CH₃CN (30.00 ml), andthe reaction mixture was stirred for 15 minutes. A solution of thecyclic sulfone intermediate C (7.47 mmol) in MeCN (30.00 ml) was addeddropwise and the solution was stirred for 12 h. To the reaction mixturewas added 0.5 N HCl (50 mL) and the solution was allowed to stir for anadditional 15 minutes. A precipitate formed after a few minutes. Thesolid was collected by filtration, washed with water (50 mL), and driedunder vacuum to yield Boc-protected intermediate as a beige solid(50-60%).

A suspension of the Boc-protected intermediate (0.77 mmol) in anhydrousMeOH (1 mL) was treated with 2.0 M HCl in diethyl ether (4.6 mmol, 5eq), and the contents were stirred at room temperature. Dissolutionoccurred, followed by precipitation of a solid. After 3 hours, thereaction mixture was diluted with diethyl ether (10 mL) and the solidwas collected by filtration, washed with diethyl ether (10 mL) and driedunder vacuum to afford D as a beige solid (65-75%).

4-hydroxybenzo[d][1,2,3]triazine-8-carboxamide (E) (Scheme 3)2-Nitroisophthalic Acid

A mixture of 2-nitro-m-xylene (10.0 g, 0.066 mol) and sodium hydroxide(2.29 g, 0.072 mol) in water (200 mL) was heated to 90° C. and potassiumpermanganate (41.0 g, 0.264 mol) was added in lot wise during a periodof 3 h. The reaction mixture was heated to 90° C. for 20 h. The reactionmass was filtered through celite bed, washed with hot water (50 mL) andacidified using 6N HCl (pH>1). The solid precipitated out were collectedby filtration, washed with water and dried under suction to afford thetitle compound as the white solid (72% yield). LC-MS [210 (M−H)], ¹H NMR(400 MHz, DMSO-d₆): δ 8.18 (d, J=7.80 Hz, 2H), 7.80 (t, J=7.80 Hz, 1H).

2-Nitro-isophthalamide

A mixture of 2-nitro-isophthalic acid (10.0 g, 0.047 mol), thionylchloride (100 mL) and DMF (0.1 mL) was heated to reflux for 16 h undernitrogen atmosphere. The reaction mixture was evaporated under reducedpressure. The residue was dissolved in THF (50 mL), cooled to 0° C. andaqueous ammonia (50 mL) was added in drops. The reaction mixture wasstirred at RT for 6 h, the solid precipitated out were collected byfiltration, washed with water and dried under suction to afford thetitle compound as the white solid (61% yield). LC-MS [208 (M−H)], ¹H NMR(400 MHz, DMSO-d₆): δ 8.28 (brs, 2H), 7.77 (brs, 2H), 7.74-7.67 (m, 3H).

2-Amino isophthalamide

A mixture of 2-nitro-isophthalamide (6 g, 0.028 mol) and Pd/C (0.6 g) inDMF (100 mL) was hydrogenated at RT under hydrogen bladder pressure for16 h. The reaction mixture was filtered through celite bed, washed withDMF and filtrate was evaporated under vacuum to afford the titlecompound as a brown solid (yield 78%). LC-MS [178 (M−H)], ¹H NMR (400MHz, DMSO-d₆): δ 7.97 (s, 2H), 7.84 (brs, 2H), 7.65 (d, J=7.76 Hz, 2H),7.22 (brs, 2H), 6.49 (t, J=7.76 Hz, 1H).

4-hydroxybenzo[d][1,2,3]triazine-8-carboxamide

A solution of 2-amino-isophthalamide (4.0 g, 0.022 mol) in DMF (40 mL)was added to a solution of sodium nitrite (1.85 g, 0.0267 mol) in 0.5 MHCl (120 mL) at 0° C. The reaction mixture was stirred at RT for 2 h andevaporated under reduced pressure. The residue was made slurry withwater and filtered, dried under suction to afford the title compound Cas a white solid (yield 84%). LC-MS [191 (M+H)], ¹H NMR (400 MHz,DMSO-d₆) δ 15.19 (s, 1H), 8.48 (s, 1H), 8.32-8.29 (m, 2H), 7.94 (dd,J=5.5, 14.4 Hz, 2H).

4-hydroxypyrido[4,3-d]pyrimidine-8-carboxamide (F) (Scheme 4) Dimethyl4-oxo-1,4-dihydropyridine-3,5-dicarboxylate

A mixture of dimethyl 3-oxopentanedioate (12 g, 69 mmol), CH(OEt)3 (15.1g, 100 mmol) and urea (6 g, 100 mmol) in xylene (25 mL) was heated toreflux for 3 hours. The mixture was cooled to room temperature and theprecipitate was filtered, washed with xylene and DCM to afford the titlecompound as white solid (yield 82.3%).

Dimethyl 4-chloropyridine-3,5-dicarboxylate

A mixture of dimethyl 4-oxo-1,4-dihydropyridine-3,5-dicarboxylate (3 g,crude) and POCl3 (10 mL) was heated to 140° C. in the sealed tube for 15hours. The mixture was cooled to RT, poured into ice and extracted withether. The organic layer was washed with brine, dried over Na2SO4,filtered and concentrated to afford the title compound as solid (yield33.7%).

Methyl 4-hydroxypyrido[4,3-d]pyrimidine-8-carboxylate

To the mixture of dimethyl 4-chloropyridine-3,5-dicarboxylate (0.6 g,2.6 mmol) and formimidamide acetate (0.82 g, 7.8 mmol) in dioxane (20mL) was added NaH (0.31 g, 7.8 mmol). The resulting mixture was refluxedfor 48 hours, cooled to RT. The precipitate was filtered, and washedwith EA to afford the title compound as grey solid (yield 56.1%).

4-hydroxypyrido[4,3-d]pyrimidine-8-carboxamide

The mixture of methyl 4-hydroxypyrido[4,3-d]pyrimidine-8-carboxylate (47mg, 0.1 mmol), NH4OH (3 mL) and MeOH (10 mL) was heated to reflux for 20hours in a sealed tube. The mixture was then concentrated and purifiedby prep-HPLC to afford the title compound as a white solid (yield41.1%).

4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) and4-hydroxypyrido[3,4-d]pyrimidine-8-carboxamide (H) (Scheme 5)3-Nitro-pyridine-2,4-dicarboxylic Acid

To a solution of sodium hydroxide (515.24 g; 12881.94 mmol) in water(15.00 l; 30.00 V) was added 2,4-Dimethyl-3-nitro-pyridine (500.00 g;3220.48 mmol). The mixture was stirred at 90° C. and potassiumpermanganate (5.25 kg; 32204.85 mmol) was added in small portions andthe mixture was heated to reflux while stirred for 16 hours. Aftercooling to room temperature, the mixture was filtered through celite andwashed with water (1 L). The filtrate was evaporated under vacuum to ½thof the original volume with resulting solution cooled ˜5° C. HCl (conc.,aq.) was added in drops and pH was adjusted to ˜2. The product wasextracted with EtOAc (5×3 L). The combined organic layer was dried overNa2SO4 and evaporated under vacuum to afford the titled compound as ayellow solid (yield 12.4%). LC-MS [167 (M+H)], ¹H NMR (400 MHz, DMSO-d6)14.2 (bs, 2H), 9.0-8.99 (d, 2H), 8.11-8.10 (d, 1H).

3-Nitro-pyridine-2,4-dicarboxylic Acid Diethyl Ester

To a solution of 3-Nitro-pyridine-2,4-dicarboxylic acid (110.00 g; 0.40mol) in DMF (1100.00 ml; 10.00 V), was added potassium carbonate (170.02g; 1.19 mol) and iodoethane (94.95 ml; 1.19 mol). The mixture wasstirred at ambient temperature for 16 hours. After completion ofreaction, the reaction mixture was filtered and the filtrate removed byconcentration under vacuum. The residue was taken in ethyl acetate (1L), filtered again and concentrated under vacuum. The residue wasdiluted with cold water (1 L) and extracted with diethyl ether (3×1 L).The combined organic layer was washed with water (2×300 mL), dried overNa₂SO₄ and concentrated under vacuum. The residue was purified by thecolumn chromatography over silica gel (60-120 mesh) using 5-10% EtOAc:Hexanes to afford the titled compound as a brown liquid (yield 51.6%).LC-MS [269 (M+H)], ¹HNMR (400 MHz, CDCl3) 8.94-8.93 (d, 1H), 8.00-7.98(d, 1H), 4.48-4.38 (m, 4H), 1.41-1.38 (m, 6H).

3-Amino-pyridine-2,4-dicarboxylic Acid Diethyl Ester

To a solution of 3-Nitro-pyridine-2,4-dicarboxylic acid diethyl ester(55.00 g; 0.19 mol) was added Palladium on carbon (10% w/w) (6.00 g;0.01 mol). The mixture was stirred at room temperature for 4 hours under5 Kg of hydrogen pressure. After completion of the reaction, thereaction mixture was filtered through celite and the filtrateconcentrated under vacuum. The residue was purified by columnchromatography (60-120 mesh) using 15-20% EtOAc: petroleum ether toafford the title compound as a yellow solid (yield 69.7%). LC-MS [239(M+H)], ¹H NMR (400 MHz, DMSO-d6), 7.94-7.93 (d, 1H), 7.84-7.83 (d, 1H),4.34-4.27 (m, 4H), 1.33-1.29 (m, 6H)

4-Hydroxy-pyrido[3,2-d]pyrimidine-8-carboxylamide (G) and4-Hydroxy-pyrido[3,4-d]pyrimidine-8-carboxylamide (H)

A solution of 3-Amino-pyridine-2,4-dicarboxylic acid diethyl ester(30.00 g; 0.13 mol) in formamide (150.00 ml; 5.00 V) was stirred at 140°C. for 4 days. The reaction mixture was cooled to 0° C. After 5 hoursstirring at 0° C., the reaction mixture was filtered and the collectedsolids were washed with water (20 mL). A slurry was made with the solidsin IPA (20 mL), filtered and again washed with IPA, then dried undersuction to afford a mixture of the title compounds (G, major product)and (H, minor product) as a gray solid (yield 50.1%). LC-MS [189 (M−H)],¹H NMR (400 MHz, DMSO-d6) 12.42 (bs, 1H), 9.33 (s, 1H), 8.88-8.87 (d,1H), 8.33 (s, 1H), 8.21-8.20 (d, 1H), 8.13 (s, 1H)

4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) (Scheme 6)4-methyl-3-nitropyridin-2(1H)-one

2-Amino-4-methyl-3-nitropyridine (120 g, 0.78 mol) was suspended inwater (1.6 L), a concentrated sulfuric acid (120 mL) was added dropwise,and the clear yellow solution was cooled to 0° C. in an ice bath. Sodiumnitrite (98 g, 1.42 mol) dissolved in water (250 mL) was added slowlybellow the liquid surface of the reaction solution through a long stemfunnel. The reaction mixture was stirred at room temperature for 2 h andwas boiled up until no further emission of a brown gas was observed. Thereaction solution was cooled, filtered, and dried to obtain the titlecompound (yield 91.6%).

2-bromo-4-methyl-3-nitropyridine

The 4-methyl-3-nitropyridin-2(1H)-one (110 g, 0.71 mol) was suspended indichloroethane (1 L). The solution of phosphorus oxybromide (317 g, 1.1mol) in dichloroethane (1 L) was added dropwise thereto at the ambienttemperature. The reaction mixture was refluxed for 12 hours. The mixturewas allowed to cool to room temperature, poured into ice water, andneutralized with potassium carbonate. The organic layer was separated,washed with water and brine, and dried over sodium sulfate. The solventwas evaporated to provide the thtile compound (yield 71.8%).

4-methyl-3-nitropicolinonitrile

The bromopyridine (110 g, 0.51 mol) and freshly prepared copper cyanide(50 g, 0.56 mol) were heated in DMF (1 L) at 100° C. for 13 hours. Thereaction mixture was allowed to cool to room temperature and poured intoa mixture EtOAc/H2O (1.5 L: 3 L). Obtained triphasic mixture wasfiltered from inorganic solid material. Organic phase was separated,washed with water and dried over sodium sulfate. The solvent wasevaporated to provide the title compound (yield 63.7%).

4-methyl-3-nitropicolinamide

The nitrile derivative (106 g, 0.65 mol) was carefully dissolved in 90%sulfuric acid (350 mL). The reaction mixture was heated at 70° C. for 3hours. Then the reaction mixture was allowed to cool to room temperatureand was poured into crushed. The precipitated amide was filtered anddried under reduced pressure (yield 59.5%).

3-amino-4-methylpicolinamide

Three-necked round bottom flask (4 L) quipped with mechanical stirredbar and condenser was charged with nitro derivative (70 g, 0.39 mol)dissolved in i-PrOH (2 L). NH4Cl (7 g), HCl (7 mL), H2O (7 mL) was addedthereto. The reaction mixture was heated up to reflux. Iron powder (156g, 2.8 mol) was added in small portions. After full consumption ofstarting material, sodium carbonate (106 g, 2.8 mol) was added in smallportions. The hot reaction mixture was filtered; insoluble material waswashed with hot ethanol several times. The solvent was evaporated toprovide the pure amineproduct (yield 61.5%).

8-methylpyrido[3,2-d]pyrimidin-4(3H)-one

The amine derivative (37 g, 0.24 mol) was refluxed in excess oftriethylorthoformate (500 mL) for 24 hours. The precipitate wascollected, washed with MTBE to obtain the title compound (yield 90.5%).

4-oxo-3,4-dihydropyrido[3,2-d]pyrimidine-8-carboxylic Acid

Two-necked round bottom flask (2 L) equipped with mechanical stirred barwas charged with 98% conc. sulfuric acid (350 mL, d=1.98). Thepyrmidinone (35 g, 217 mmol) was carefully added to the mixture.Potassium dichromate (95.8 g, 0.33 mol) was added portionwise toreaction mixture maintaining the temperature between 20-30° C. Thereaction mixture was stirred at room temperature overnight. Crushed ice(1.5 kg) was added to the reaction mixture in small portions maintainingthe temperature in the 20-30° C. range. Potassium carbonate was addedportionwise to pH 1. The formed precipitate was filtered, washed withwater and dried under reduced pressure to the title compound (yield72.4%).

4-Hydroxy-pyrido[3,2-d]pyrimidine-8-carboxylamide

The acid intermediate (8.3 g, 43 mmol) was dissolved in DMF (200 mL) andCDI (8.8 g, 54 mmol) was added thereto. The reaction mixture was warmedto 70° C. and gas evolution was observed. After completion gas evolutionthe reaction mixture was heated at the same temperature for additionalhour to provide a clear solution. Aqueous 25% ammonia (30 ml, 10 eq.)was added and the reaction mixture was heated at 70° C. overnight. Thereaction mixture was allowed to cool to room temperature and the solventwas evaporated under reduced pressure. The residue was diluted withwater, filtered, washed with water and dried under reduced pressure toprovide the title compound (yield 81.9%).

Methyl 4-hydroxypyrido[3,4-d]pyrimidine-8-carboxylate (I) (Scheme 6)

The 4-oxo-3,4-dihydropyrido[3,2-d]pyrimidine-8-carboxylic acid (39.0 g,0.20 mol) was dissolved in anhydrous NMP (700 mL) and CDI (41.3 g, 0.26mol, 10 eq.) was added. The reaction mixture was warmed to 70° C. andgas evolution was observed. After completion gas evolution the reactionmixture was heated at the same temperature for additional hour toprovide a clear solution. Methanol (65 g, 2 mol) was added thereto andthe reaction mixture was heated at 70° C. overnight. The reactionmixture was allowed to cool to room temperature and the organic materialwas precipitated. It was filtered, washed with methanol and dried underreduced pressure to provide the title compound (I) (yield 75.0%).

4-substituted-aza-quinazolin-8-carboxamide (L) (Scheme 7)

A mixture of aza-quinazoline carboxamide J (0.21 mmol), amineintermediate K (0.21 mmol), and DIEA (0.86 mmol) were suspended in thesolvent (DMF or NMP or DMSO) (2.00 mL) under Ar. The reaction mixturewas stirred at rt for 5 min before the addition of PyBOP (0.59 mmol).The reaction was stirred at room temperature for 12 h. The reactionmixture was diluted with water (10 mL) and extracted with EtOAc (3×10mL). The combined organics were dried over sodium sulfate andconcentrated. The residue was purified by either reverse phase HPLC orBiotage to give the desired product L as an off-white solid (11-40%).

4-substituted-aza-quinazolin-8-carboxamide (M) (Scheme 8)

A mixture of nosyl-protected amine D (0.34 mmol), aza-quinazolinecarboxamide J (0.44 mmol), and DIEA (0.68 mmol) were suspended in DMSO(3.00 mL) under Ar. The reaction mixture was stirred at rt for 5 minbefore addition of PyBOP (0.44 mmol). The reaction was stirred at 40° C.for 12 h. The reaction mixture was filtered and purified by eitherreverse phase HPLC or Biotage to give the desired nosyl-protectedintermediate as an off-white solid (40-92%).

To the solution of the nosyl-protected intermediate (0.38 mmol) in DMF(3.00 ml) was added potassium carbonate (1.13 mmol) and the suspensionwas stirred for 10 minutes.

Benzenethiol (1.51 mmol) was added via syringe and the solution wasstirred vigorously at room temperature overnight. The reaction mixturewas filtered and purified by either reverse phase HPLC or Biotage togive the desired product M as a white solid (65-85%).

4-substituted-aza-quinazolin-8-carboxamide (0) (Scheme 9)

A mixture of Boc-protected amine N (0.53 mmol), aza-quinazolinecarboxamide J (0.53 mmol), DIEA (1.58 mmol) and PyBOP (0.79 mmol) weresuspended in DMSO (2.00 mL) under Ar. The reaction was stirred at 50° C.for 18 h. The reaction mixture was partitioned between EtOAc (25 mL) andsaturated sodium bicarbonate solution (5 mL) and phases were separated.The organic phase was washed 4× with water (5 mL) and with brine. Theorganic layer was dried with sodium sulfate, filtered and concentrated.The reaction mixture was purified on Si-gel with Biotage (EtOAC/hexanes)to give the desired Boc-protected intermediate as an off-white solid(26-48%).

To the solution of the Boc-protected intermediate (0.12 mmol) inmethanol (1.5 ml) at room temperature was added 4N HCl in 1,4-dioxane(0.50 mL) and the suspension was stirred for 1 hour. The reactionmixture was filtered and purified by reverse phase HPLC to give thedesired products O as a white solid (44-72%).

4-substituted-aza-quinazolin-8-carboxamide (M) (Scheme 10)

A mixture of methyl aza-quinazoline carboxylate (2.4 mmol), DIEA (4.8mmol) and PyBOP (2.9 mmol) were suspended in DMSO (10 mL) under Ar. Thereaction mixture was stirred at rt for 10 min before the addition ofnosyl-protected amine (2.4 mmol). The reaction was stirred at 40° C.overnight. After cooling to RT, the reaction was diluted with EtOAc andwashed with saturated sodium bicarbonate solution. The separated organicphase was washed with 1M HCl (1×), followed by water (4×), and thenbrine (1×). The organic phase was dried over Na2SO4, filtered andconcentrated in vacuo to give the crude, which was purified on Biotageto give the desired methyl ester intermediate as an light yellow foam(50-65%).

The reaction mixture of the methyl ester intermediate (1.5 mmol) in 7Nammonia in MeOH (12 mL) was stirred at rt overnight. The reactionmixture was concentrated to yield the desired nosyl-protected amideintermediate (80-85%).

To the solution of the nosyl-protected amide intermediate (0.6 mmol) inacetonitrile (2 mL) was added DBU (1.8 mmol) and mercaptoacetic acid(0.9 mmol). The reaction mixture was stirred at room temperatureovernight. The reaction was concentrated and dissolved in DCM, which waswashed with saturated sodium bicarbonate solution followed by brine. Theorganic layer was dried over sodium sulfate, filtered and concentratedto yield the crude product. The desired amide M was then isolated viatrituration with dichloromethane to give an off-white solid (70-85%).

4-substituted-aza-quinazolin-8-carboxamide (Q) (Scheme 11)

The aza-quinazoline carboxamide J (1.92 mmol) was refluxed in phosphorylchloride (215 mmol) for 12-18 hours. Upon completion, the reaction wasconcentrated en vacuo by rotary evaporation. The residue was then takenup in cold ethyl acetate and washed with ice cold saturated sodiumbicarbonate solution. The organic layer was washed with brine, driedover sodium sulfate, filtered and concentrated to yield the desiredbicyclic chloride intermediate as a yellow solid (34-94%).

The amine (8.43 mmol) was suspended in acetonitrile (85 mL) in a clean,dry round bottom flask equipped a magnetic stir bar. To this was addedHunig's base (50 mmol) and sodium sulfate (28 mmol). The resultantsuspension was stirred for 5 minutes, then the bicyclic chlorideintermediate (8.43 mmol) was added. The reaction mixture was stirred andheated to 40° C. for 12-18 hours. Upon completion, the reaction wasconcentrated en vacuo by rotary evaporation. The residue was purified byflash chromatography on silica under 20-50% ethyl acetate in hexanes toyield the desire nitrile intermediate as a light yellow solid (24-60%).

To a mixture of nitrile intermediate (1.37 mmol) and sodium hydroxide(5.46 mmol) in isopropyl alcohol (5.00 ml) and minimal DMSO (0.5 mL) wasadded hydrogen peroxide (8.2 mmol) at room temperature. The mixture wasstirred for until completion. The desired amide compound Q was isolatedby diluting the reaction mixture with water (20 mL) then filtering thesolids (75-95%).

4-substituted-aza-quinazolin-8-carboxamide (M) (Scheme 11)

To the solution of the nosyl protected amide intermediate (5.74 mmol) inacetonitrile (15 mL) was added DBU (17.2 mmol) and mercaptoacetic acid(8.61 mmol). The reaction mixture was stirred at room temperature. Uponcompletion, the reaction was concentrated and taken up indichloromethane, washed with saturated sodium bicarbonate solutionfollowed by brine solution. The organic layer was then dried over sodiumsulfate, filtered and concentrated to yield the crude product. Thedesired amide M was then isolated via trituration with dichloromethaneto give an off-white solid (57-95%).

Example 2: Synthesis of Compounds of the Invention

4-(3-Trifluoromethyl-benzylamino)-benzo[d][1,2,3]triazine-8-carboxamide(1)

Compound 1 was prepared following general synthetic scheme 7 wherein3-trifluoromethyl-benzylamine was reacted with4-hydroxybenzo[d][1,2,3]triazine-8-carboxamide to give the titlecompound. LC-MS [348 (M+1)], ¹HNMR (400 MHz, DMSO-d₆): δ 9.36-9.33 (m,2H), 8.55-8.49 (m, 2H), 8.04 (s, 1H), 8.02-7.98 (m, 1H), 7.80 (s, 1H),7.72 (d, 1H), 7.64 (d, 1H), 7.59-7.56 (m, 1H), 5.00 (d, 2H).

4-((3,4-dichlorobenzyl)amino)benzo[d][1,2,3]triazine-8-carboxamide (2)

Compound 2 was prepared following general synthetic scheme 7 wherein(3,4-dichlorophenyl)methanamine was reacted with4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the titlecompound. LC-MS [350 (M+1)], ¹H NMR (400 MHz, DMSO-d6): δ 9.37 (s, 1H),9.31 (t, 1H), 8.54 (d, 1H), 8.49 (d, 1H), 8.05 (s, 1H), 8.00 (t, 1H),7.70 (s, 1H), 7.60 (d, 1H), 7.40 (d, 1H), 4.90 (d, 1H).

4-((pyridin-3-ylmethyl)amino)benzo[d][1,2,3]triazine-8-carboxamide (3)

Compound 3 was prepared following general synthetic scheme 7 whereinpyridin-3-ylmethanamine was reacted with4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the titlecompound. LC-MS [281 (M+1)], ¹H NMR (400 MHz, DMSO-d): δ 9.38-9.32 (m,2H), 8.66 (s, 1H), 8.54 (d, 1H), 8.50-8.48 (m, 2H), 8.05 (s, 1H), 7.99(t, 1H), 7.82 (d, 1H), 7.38-7.35 (m, 1H), 4.93 (s, 2H).

4-((4-chloro-3-(trifluoromethyl)benzyl)amino)benzo[d][1,2,3]triazine-8-carboxamide(4)

Compound 4 was prepared following general synthetic scheme 7 wherein(4-chloro-3-(trifluoromethyl)phenyl)methanamine was reacted with4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the titlecompound. LC-MS [382 (M+1)], ¹H NMR (400 MHz, DMSO-d): δ 9.38-9.32 (m,2H), 8.54 (d, 1H), 8.48 (d, 1H), 8.05 (s, 1H), 8.02-7.98 (m, 1H), 7.95(s, 1H), 7.73-7.68 (m, 2H), 4.96 (d, 2H).

4-((pyridin-2-ylmethyl)amino)benzo[d][1,2,3]triazine-8-carboxamide (5)

Compound 5 was prepared following general synthetic scheme 7 whereinpyridin-2-ylmethanamine was reacted with4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the titlecompound. LC-MS [281 (M+1)], ¹H NMR (400 MHz, DMSO-d): δ 9.40 (s, 2H),8.56-8.51 (m, 3H), 8.04 (s, 1H), 8.00 (t, 1H), 7.76-7.72 (m, 1H), 7.40(d, 1H), 7.29-7.26 (m, 1H), 4.99 (d, 2H).

4-(benzylamino)benzo[d][1,2,3]triazine-8-carboxamide (6)

Compound 6 was prepared following general synthetic scheme 7 whereinbenzylamine was reacted with4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the titlecompound. LC-MS [280 (M+1)], ¹H NMR (400 MHz, DMSO-d): δ 9.42 (s, 1H),9.31 (t, 1H), 8.53 (t, 1H), 8.04 (s, 1H), 7.98 (t, 1H), 7.41 (d, 2H),7.34 (t, 2H), 7.28-7.24 (m, 1H), 4.92 (d, 2H).

4-(((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)benzo[d][1,2,3]triazine-8-carboxamide(7)

Compound 7 was prepared following general synthetic scheme 7 wherein(5-(trifluoromethyl)-pyridin-2-yl)methanamine was reacted with4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the titlecompound. LC-MS [349 (M+1)], ¹H NMR (400 MHz, DMSO-d): δ 9.50 (t, 1H),9.35 (s, 1H), 8.93 (s, 1H), 8.55 (d, 2H), 8.16 (dd, 1H), 8.05-8.01 (m,2H), 7.65 (d, 1H), 5.07 (d, 2H).

4-((4-(trifluoromethyl)benzyl)amino)benzo[d][1,2,3]triazine-8-carboxamide(8)

Compound 8 was prepared following general synthetic scheme 7 wherein(4-(trifluoromethyl)phenyl)methanamine was reacted with4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the titlecompound. LC-MS [348 (M+1)], ¹H NMR (400 MHz, DMSO-d): δ 9.40-9.37 (m,2H), 8.56-8.51 (m, 2H), 8.05 (s, 1H), 8.01 (t, 1H), 7.70 (d, 2H), 7.62(d, 2H), 4.99 (d, 2H).

4-((3-fluorobenzyl)amino)benzo[d][1,2,3]triazine-8-carboxamide (9)

Compound 9 was prepared following general synthetic scheme 7 wherein(3-fluorophenyl)methanamine was reacted with4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the titlecompound. LC-MS [298 (M+1)], ¹H NMR (400 MHz, DMSO-d6): 9.39 (s, 1H),9.32 (s, 1H), 8.55-8.50 (m, 2H), 8.05 (s, 1H), 7.99 (t, 1H), 7.41-7.35(m, 1H), 7.26-7.23 (m, 2H), 7.11-7.09 (m, 1H), 4.93 (d, 2H).

(S)-4-((2-(azetidin-1-yl)-1-(4-chloro-3-methoxyphenyl)ethyl)amino)-benzo[d][1,2,3]triazine-8-carboxamide(10)

Compound 10 was prepared following general synthetic scheme 7 wherein(S)-2-(azetidin-1-yl)-1-(4-chloro-3-methoxyphenyl)ethanamine was reactedwith 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the titlecompound. LC-MS [413 (M+1)], ¹H NMR (400 MHz, DMSO-d6): δ 10.01 (s, 1H),9.29 (s, 1H), 9.08 (d, 1H), 8.58 (d, 2H), 8.08 (t, 2H), 7.44 (d, 2H),7.15 (dd, 1H), 6.05-6.00 (m, 1H), 4.44-4.41 (m, 1H), 4.26-4.22 (m, 1H),4.21-4.05 (m, 2H), 3.89 (s, 3H), 3.80-3.74 (m, 3H), 2.49-2.40 (m, 2H).

(S)-4-((1-(4-chloro-3-methoxyphenyl)-2-(dimethylamino)ethyl)amino)-benzo[d][1,2,3]triazine-8-carboxamide(11)

Compound 11 was prepared following general synthetic scheme 7 wherein(S)-1-(4-chloro-3-methoxyphenyl)-N2,N2-dimethylethane-1,2-diamine wasreacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give thetitle compound. LC-MS [401 (M+1)], ¹H NMR (400 MHz, DMSO-d6): δ 9.51 (s,1H), 9.27 (s, 1H), 9.09 (d, 1H), 8.58 (dd, 2H), 8.08 (t, 2H), 7.44 (d,2H), 7.18 (dd, 1H), 6.26 (t, 1H), 3.89 (s, 3H), 3.83-3.76 (m, 1H),3.62-3.57 (m, 1H), 2.92 (d, 6H).

(S)-4-((2-(azetidin-1-yl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)benzo[d][1,2,3]triazine-8-carboxamide(12)

Compound 12 was prepared following general synthesis scheme 7 wherein4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide was reacted with(S)-2-(azetidin-1-yl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanamineto give the title compound as a white solid. LC-MS [435 (M+1)].

(S)-4-((1-(4-chloro-3-(trifluoromethyl)phenyl)-2-(dimethylamino)ethyl)amino)benzo-[d][1,2,3]triazine-8-carboxamide(13)

Compound 13 was prepared following general synthetic scheme 7 wherein(S)-1-(4-Chloro-3-(trifluoromethyl)phenyl)-N2,N2-dimethylethane-1,2-diaminewas reacted with 4-hydroxybenzo[d][1,2,3]triazine-8-carboxamide to givethe title compound. LC-MS [439 (M+1)], ¹H NMR (400 MHz, DMSO-d6): δ 9.61(brs, 1H), 9.23 (s, 1H), 9.17 (s, 1H), 8.58 (s, 2H), 8.19 (s, 1H), 8.08(d, J=8.0 Hz, 2H), 7.92 (s, 1H), 7.78 (d, J=7.2 Hz, 1H), 6.34 (s, 1H),3.83-3.63 (m, 2H), 2.91 (s, 6H).

(S)-4-((2-(azetidin-1-yl)-1-(4-chloro-3-(trifluoromethyl)phenyl)ethyl)amino)benzo[d][1,2,3]triazine-8-carboxamide(14)

Compound 14 was prepared following general synthetic scheme 7 wherein(S)-2-(Azetidin-1-yl)-1-(4-chloro-3-(trifluoromethyl)phenyl)ethan-1-aminewas reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to givethe title compound. LC-MS [451 (M+1)], ¹H NMR (400 MHz, DMSO-d6): δ 9.30(s, 1H), 8.87 (d, 1H), 8.63 (d, 1H), 8.54 (d, 1H), 8.05-8.01 (m, 3H),7.81 (d, 1H), 7.70 (d, 1H), 5.59 (d, 1H), 3.21-3.14 (m, 4H), 3.02 (t,1H), 2.99-2.78 (m, 1H), 1.92 (t, 2H).

(S)-4-((1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)amino)benzo[d][1,2,3]triazine-8-carboxamide(15)

Compound 15 was prepared following general synthetic scheme 7 wherein(S)-1-(3,4-dichlorophenyl)-N2,N2-dimethylethane-1,2-diamine was reactedwith 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the titlecompound. LC-MS [407 (M+1)], ¹H NMR (400 MHz, DMSO-d6): δ 9.63 (s, 1H),9.24 (s, 1H), 9.12 (d, 1H), 8.59-8.56 (m, 2H), 8.10-8.06 (m, 2H), 7.95(d, 1H), 7.69 (d, 1H), 7.60 (dd, 1H), 6.25 (t, 1H), 3.80 (t, 1H),3.61-3.59 (m, 1H), 2.91 (d, 6H).

(S)-4-((2-(azetidin-1-yl)-1-(3,4-dichlorophenyl)ethyl)amino)benzo[d][1,2,3]triazine-8-carboxamide(16)

Compound 16 was prepared following general synthetic scheme 7 wherein(S)-2-(Azetidin-1-yl)-1-(3,4-dichlorophenyl)ethanamine was reacted with4-hydroxybenzo[d][1,2,3]triazine-8-carboxamide to give the titlecompound. LC-MS [417 (M+1)].

(S)-4-((1-(4-chloro-3-cyanophenyl)-2-(dimethylamino)ethyl)amino)-benzo[d][1,2,3]triazine-8-carboxamide(17)

Compound 17 was prepared following general synthetic scheme 7 wherein(S)-5-(1-amino-2-(dimethylamino)ethyl)-2-chlorobenzonitrile was reactedwith 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the titlecompound. LC-MS [397 (M+1)], ¹H NMR (400 MHz, DMSO-d6): δ 9.31 (s, 1H),8.81 (d, 1H), 8.63 (d, 1H), 8.55 (d, 1H), 8.15 (d, 1H), 8.05-8.01 (m,2H), 7.88 (dd, 1H), 7.72 (d, 1H), 5.78 (q, 1H), 2.95-2.89 (m, 1H),2.62-2.58 (m, 1H), 2.24 (s, 6H).

(S)-4-((2-(azetidin-1-yl)-1-(4-chloro-3-cyanophenyl)ethyl)amino)benzo[d][1,2,3]triazine-8-carboxamide(18)

Compound 18 was prepared following general synthetic scheme 7 wherein(S)-5-(1-amino-2-(azetidin-1-yl)ethyl)-2-chlorobenzonitrile was reactedwith 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the titlecompound. LC-MS [408 (M+1)], ¹H NMR (400 MHz, DMSO-d6): δ 9.31 (s, 1H),8.82 (d, 1H), 8.63 (d, 1H), 8.55 (d, 1H), 8.12 (d, 1H), 8.03 (t, 2H),7.85 (dd, 1H), 7.72 (d, 1H), 5.54 (d, 1H), 3.21-3.12 (m, 4H), 3.02-2.97(m, 1H), 2.83-2.79 (m, 1H).

(R)-4-((2-(azetidin-1-yl)-1-(4-chloro-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidine-8-carboxamide(19)

Compound 19 was prepared following general synthetic scheme 7 wherein(R)-2-(azetidin-1-yl)-1-(4-chloro-3-(trifluoromethyl)phenyl)ethanaminewas reacted with 4-hydroxypyrido[4,3-d]pyrimidine-8-carboxamide to givethe title compound as an off-white solid. LC-MS [451 (M+1)], ¹H NMR (400MHz, Chloroform-d) δ 10.43 (s, 1H), 9.75 (s, 1H), 9.59 (s, 1H), 8.62 (s,1H), 7.98 (s, 1H), 7.69 (s, 1H), 7.48 (d, 2H), 6.12 (s, 1H), 5.18 (d,1H), 3.25 (dq, 4H), 3.05-2.89 (m, 2H), 2.14 (p, 2H).

(S)-4-((2-(azetidin-1-yl)-1-(4-chloro-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidine-8-carboxamide(20)

Compound 20 was prepared following general synthetic scheme 7 wherein(S)-2-(azetidin-1-yl)-1-(4-chloro-3-(trifluoromethyl)phenyl)ethanaminewas reacted with 4-hydroxypyrido[4,3-d]pyrimidine-8-carboxamide to givethe title compound. LC-MS [451 (M+1)], ¹H NMR (400 MHz, Chloroform-d) δ10.43 (s, 1H), 9.75 (s, 1H), 9.59 (s, 1H), 8.62 (s, 1H), 7.98 (s, 1H),7.69 (s, 1H), 7.48 (d, 2H), 6.12 (s, 1H), 5.18 (d, 1H), 3.25 (dq, 4H),3.05-2.89 (m, 2H), 2.14 (p, 2H).

4-((4-(3-(trifluoromethyl)phenyl)piperidin-3-yl)amino)benzo[d][1,2,3]triazine-8-carboxamide(21)

Compound 21 was prepared following general synthesis scheme 9 wherein4-hydroxybenzo[d][1,2,3]triazine-8-carboxylic acid amide was reactedwith tert-butyl3-amino-4-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate to givethe title compound. LC-MS [417 (M+H)], ¹H NMR (400 MHz, DMSO-d6) δ 9.24(s, 1H), 8.98 (d, 1H), 8.84 (t, 1H), 8.54 (d, 1H), 8.50 (d, 1H), 8.30(d, 1H), 8.04-7.89 (m, 2H), 7.67 (s, 1H), 7.59 (t, 1H), 7.45 (d, 2H),5.42-5.26 (m, 1H), 3.64 (d, 1H), 3.49 (d, 1H), 3.35 (td, 1H), 3.23-2.90(m, 2H), 2.52-2.00 (m, 2H).

4-((4-(4-(trifluoromethyl)phenyl)piperidin-3-yl)amino)benzo[d][1,2,3]triazine-8-carboxamide(22)

Compound 22 was prepared following general synthesis scheme 9 wherein4-hydroxybenzo[d][1,2,3]triazine-8-carboxylic acid amide was reactedwith tert-butyl3-amino-4-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate to givethe title compound. LC-MS [417 (M+H)], ¹H NMR (400 MHz, DMSO-d6) δ 9.21(s, 1H), 9.04-8.92 (m, 1H), 8.61-8.43 (m, 3H), 8.11-7.92 (m, 2H), 7.72(d, 1H), 7.64-7.46 (m, 5H), 5.58-5.44 (m, 1H), 3.71-3.44 (m, 4H),3.30-3.09 (m, 1H), 2.81-2.60 (m, 1H), 2.08 (d, 1H).

4-[4-(3-Chloro-4-fluoro-phenyl)-piperidin-3-ylamino]-pyrido[3,2-d]pyrimidine-8-carboxamide(23)

Compound 23 was prepared following general synthesis scheme 9 wherein4-hydroxy-pyrido[3,2-d]pyrimidine-8-carboxylic acid amide was reactedwith tert-butyl3-amino-4-(3-chloro-4-fluoro-phenyl)piperidine-1-carboxylate to give thetitle compound. LC-MS [401 (M+H)].

4-((4-(3-(trifluoromethyl)phenyl)piperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide(24)

Compound 24 was prepared following general synthesis scheme 9 wherein4-hydroxy-pyrido[3,2-d]pyrimidine-8-carboxylic acid amide was reactedwith tert-butyl3-amino-4-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate to givethe title compound. LC-MS [417 (M+H)], ¹H NMR (400 MHz, DMSO-d6) δ 9.78(d, 1H), 9.06 (d, 1H), 9.03-8.95 (m, 1H), 8.90 (d, 1H), 8.88-8.73 (m,1H), 8.50 (s, 1H), 8.32 (d, 1H), 8.16 (d, 1H), 7.62 (s, 1H), 7.56 (q,1H), 7.43 (d, 2H), 5.22-5.02 (m, 1H), 3.60-3.38 (m, 3H), 3.14 (q, 1H),2.99 (q, 1H), 2.54 (d, 1H), 2.08 (dt, 2H).

4-((4-(4-(trifluoromethyl)phenyl)piperidin-3-yl)amino)pyrido[3,2-d]pyrimidine-8-carboxamide(25)

Compound 25 was prepared following general synthesis scheme 9 wherein4-hydroxy-pyrido[3,2-d]pyrimidine-8-carboxylic acid amide was reactedwith tert-butyl3-amino-4-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate to givethe title compound. LC-MS [417 (M+H)], ¹H NMR (400 MHz, DMSO-d6) δ 9.77(d, 1H), 8.99 (d, 1H), 8.93-8.82 (m, 1H), 8.82-8.70 (m, 1H), 8.65 (d,1H), 8.36 (d, 2H), 8.16 (d, 1H), 7.48 (t, 4H), 5.37-5.21 (m, 1H),3.75-3.42 (m, 1H), 3.26-3.06 (m, 1H), 2.02 (d, 1H).

4-[(S)-1-(3-Fluoro-4-trifluoromethyl-phenyl)-2-methylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (26)

Compound 26 was prepared following general synthesis scheme 8 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound as a white solid. LC/MS [409(M+H)]; ¹H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.20 (s, 1H), 9.01(dd, J=4.7, 1.7 Hz, 1H), 8.54 (d, J=1.7 Hz, 1H), 8.45-8.34 (m, 1H),8.25-8.10 (m, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.61 (d, J=12.1 Hz, 1H), 7.49(d, J=8.1 Hz, 1H), 5.53 (t, J=6.5 Hz, 1H), 3.21-3.08 (m, 1H), 3.05-2.88(m, 1H), 2.30 (s, 3H), 2.01 (s, 1H).

4-[(S)-2-Azetidin-1-yl-1-(4-trifluoromethyl-phenyl)-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (27)

Compound 27 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with(S)-2-Azetidin-1-yl-1-(4-trifluoromethyl-phenyl)-ethylaminedihydrochloride to give the title compound as a white solid. LC/MS [417(M+H)]; ¹H NMR (400 MHz, DMSO-d6) δ 9.92 (d, J=3.4 Hz, 1H), 9.11 (d,J=7.9 Hz, 1H), 9.01 (dd, J=4.5, 1.0 Hz, 1H), 8.53 (s, 1H), 8.38 (dd,J=4.5, 1.0 Hz, 1H), 8.16 (d, J=3.4 Hz, 1H), 7.83-7.50 (m, 3H), 5.36 (q,J=7.2 Hz, 1H), 3.21-2.99 (m, 4H), 2.84 (dd, J=12.0, 5.6 Hz, 1H), 1.92(p, J=6.9 Hz, 2H).

4-[(S)-1-(3-Bromo-4-fluoro-phenyl)-2-methylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (28)

Compound 28 was prepared following general synthesis scheme 8 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(3-bromo-4-fluoro-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound as a beige solid. LC/MS [419(M+H)]; ¹H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.40 (d, 1H), 9.02(dd, 1.9 Hz, 1H), 8.60 (d, 1H), 8.40 (dd, 1H), 8.19 (s, 1H), 8.04-7.76(m, 1H), 7.55 (ddd, 4.7, 2.1 Hz, 1H), 7.36 (td, 1H), 5.88-5.57 (m, 1H),3.48 (t, 1H), 3.21 (dd, 1H), 2.54 (d, 1H), 2.50 (s, 3H).

4-[(S)-2-Ethylamino-1-(3-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (29)

Compound 29 was prepared following general synthesis scheme 8 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-N-ethyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound as a pale yellow solid. LC/MS[423 (M+H)]; ¹H NMR (400 MHz, DMSO-d6) δ 9.93 (d, J=3.7 Hz, 1H), 9.25(d, J=7.8 Hz, 1H), 9.01 (d, J=4.5 Hz, 1H), 8.54 (s, 1H), 8.39 (d, J=4.5Hz, 1H), 8.19 (d, J=3.8 Hz, 1H), 7.73 (t, J=7.9 Hz, 1H), 7.62 (d, J=12.0Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 5.51 (q, J=4.9 Hz, 1H), 3.20 (dd,J=12.5, 8.1 Hz, 1H), 3.03 (dd, J=12.4, 5.2 Hz, 1H), 2.70-2.53 (m, 2H),0.99 (t, J=7.1 Hz, 3H).

4-[(S)-1-(3-Bromo-4-fluoro-phenyl)-2-ethylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (30)

Compound 30 was prepared following general synthesis scheme 8 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(3-bromo-4-fluoro-phenyl)-ethyl]-N-ethyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound as a white solid. LC/MS [434(M+H)]; ¹H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.36 (s, 1H), 9.02 (d,J=4.5 Hz, 1H), 8.60 (s, 1H), 8.40 (d, J=4.4 Hz, 1H), 8.18 (s, 1H), 7.87(d, J=4.9 Hz, 1H), 7.53 (d, J=5.5 Hz, 1H), 7.35 (t, J=8.7 Hz, 1H),5.78-5.51 (m, 1H), 3.55-3.36 (m, 1H), 3.23-3.10 (m, 1H), 2.93-2.69 (m,2H), 1.08 (t, J=7.0 Hz, 3H).

4-[(S)-1-(2,5-Difluoro-4-methoxy-phenyl)-2-ethylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (31)

Compound 31 was prepared following general synthesis scheme 8 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(2,5-difluoro-4-methoxy-phenyl)-ethyl]-N-ethyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound as a pale yellow solid. LC/MS[403 (M+H)]; ¹H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.03 (d, J=26.0Hz, 1H), 8.98 (s, 1H), 8.56 (s, 1H), 8.37 (d, J=4.5 Hz, 1H), 8.16 (s,1H), 7.40 (dd, J=12.1, 7.0 Hz, 1H), 7.09 (dd, J=11.5, 7.3 Hz, 1H), 5.69(s, 1H), 3.82 (s, 3H), 3.13 (dd, J=12.3, 8.5 Hz, 1H), 2.91 (dd, J=12.4,5.2 Hz, 1H), 2.63-2.53 (m, 2H), 1.85 (s, 1H), 0.97 (t, J=7.1 Hz, 3H).

4-[(S)-1-(2,5-Difluoro-4-methoxy-phenyl)-2-methylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (32)

Compound 32 was prepared following general synthesis scheme 8 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(2,5-difluoro-4-methoxy-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound as a white solid. LC/MS [389(M+H)]; ¹H NMR (400 MHz, DMSO-d6) δ 10.03-9.86 (m, 1H), 9.04 (s, 1H),8.98 (d, J=4.5 Hz, 1H), 8.56 (s, 1H), 8.37 (d, J=4.5 Hz, 1H), 8.24-8.07(m, 1H), 7.42 (dd, J=12.1, 7.0 Hz, 1H), 7.09 (dd, J=11.5, 7.2 Hz, 1H),5.72 (s, 1H), 3.82 (s, 3H), 3.11 (dd, J=12.3, 8.5 Hz, 1H), 2.85 (dd,J=12.4, 5.3 Hz, 1H), 2.54 (s, 1H), 2.30 (s, 3H).

4-[(S)-1-(4-Chloro-3-trifluoromethyl-phenyl)-2-ethylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (33)

Compound 33 was prepared following general synthesis scheme 8 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-N-ethyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound as a beige solid. LC/MS [439(M+H)]; ¹H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.27 (s, 1H), 9.00 (d,J=4.5 Hz, 1H), 8.54 (s, 1H), 8.38 (d, J=4.5 Hz, 1H), 8.16 (s, 1H), 8.00(d, J=1.8 Hz, 1H), 7.76 (dd, J=8.3, 1.9 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H),5.51 (s, 1H), 3.17 (dd, J=12.4, 8.0 Hz, 1H), 3.00 (dd, J=12.4, 5.6 Hz,1H), 2.60-2.55 (m, 2H), 2.54 (s, 1H), 0.97 (t, J=7.1 Hz, 3H).

4-[(S)-2-Ethylamino-1-(3-fluoro-5-trifluoromethyl-phenyl)-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (34)

Compound 34 was prepared following general synthesis scheme 8 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-N-ethyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound as a pale yellow solid. LC/MS[423 (M+H)]; ¹H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.24 (s, 1H),9.01 (d, J=4.5 Hz, 1H), 8.55 (s, 1H), 8.38 (d, J=4.4 Hz, 1H), 8.16 (s,1H), 7.74 (s, 1H), 7.66 (d, J=9.8 Hz, 1H), 7.53 (d, J=8.9 Hz, 1H),5.73-5.28 (m, 1H), 3.28 (s, 1H), 3.23-3.10 (m, 1H), 3.06-2.93 (m, 1H),2.56 (d, J=7.1 Hz, 2H), 0.97 (t, J=7.2 Hz, 3H).

4-[(S)-1-(3-Fluoro-5-trifluoromethyl-phenyl)-2-methylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (35)

Compound 35 was prepared following general synthesis scheme 8 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound as a white solid. LC/MS [409(M+H)]; ¹H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.25 (s, 1H), 9.01 (d,J=4.5 Hz, 1H), 8.55 (s, 1H), 8.38 (d, J=4.5 Hz, 1H), 8.16 (s, 1H), 7.74(s, 1H), 7.67 (d, J=9.3 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 5.57 (s, 1H),3.15 (dd, J=12.3, 8.3 Hz, 1H), 2.95 (dd, J=12.3, 5.5 Hz, 1H), 2.30 (s,3H).

4-[(S)-2-Azetidin-1-yl-1-(4-chloro-phenyl)-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (36)

Compound 36 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with(S)-2-Azetidin-1-yl-1-(4-chloro-phenyl)-ethylamine dihydrochloride togive the title compound as an off-white solid. LC/MS [383 (M+H)]; ¹H NMR(500 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.27-8.84 (m, 2H), 8.53 (s, 1H), 8.37(d, J=4.4 Hz, 1H), 8.17 (s, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.4Hz, 2H), 5.37-4.98 (m, 2H), 3.16-2.94 (m, 3H), 2.78 (dd, J=11.9, 5.3 Hz,1H), 2.07-1.65 (m, 2H).

4-[(S)-2-Azetidin-1-yl-1-(4-isopropyl-phenyl)-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (37)

Compound 37 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with(S)-2-Azetidin-1-yl-1-(4-isopropyl-phenyl)-ethylamine dihydrochloride togive the title compound as an off-white solid. LC/MS [391 (M+H)]; 1H NMR(500 MHz, DMSO-d6) δ 9.97 (s, 1H), 9.38-8.87 (m, 2H), 8.53 (s, 1H), 8.37(d, J=4.4 Hz, 1H), 8.17 (s, 1H), 7.37 (d, J=8.0 Hz, 2H), 7.17 (d, J=8.0Hz, 2H), 5.60-4.97 (m, 1H), 3.16-2.99 (m, 5H), 2.89-2.77 (m, 1H), 2.74(dd, J=11.9, 4.9 Hz, 1H), 2.02-1.72 (m, 2H), 1.16 (d, J=6.8 Hz, 6H).

4-[(S)-2-Methylamino-1-(4-trifluoromethyl-phenyl)-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (38)

Compound 38 was prepared following general synthesis scheme 8 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(4-trifluoromethyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound as a white solid. LC/MS [391(M+H)]; ¹H NMR (500 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.21 (s, 1H), 9.00 (d,J=4.4 Hz, 1H), 8.52 (s, 1H), 8.38 (d, J=4.4 Hz, 1H), 8.17 (s, 1H), 7.68(s, 4H), 5.53 (s, 1H), 3.20-3.07 (m, 1H), 2.94 (dd, J=12.2, 4.9 Hz, 1H),2.30 (s, 3H).

4-[(S)-1-(4-Isopropyl-phenyl)-2-methylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (39)

Compound 39 was prepared following general synthesis scheme 8 wherein amixture of 4-Hydroxy-pyrido[3,2-d]pyrimidine-8-carboxylamide (G) and4-Hydroxy-pyrido[3,4-d]pyrimidine-8-carboxylamide (H) was reacted withN—[(S)-2-Amino-2-(4-isopropyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamidehydrochloride. The title compound was isolated as the major product(white solid). LC/MS [365 (M+H)]; ¹H NMR (500 MHz, DMSO-d6) δ 9.92 (s,1H), 9.47 (d, J=8.6 Hz, 1H), 9.03 (d, J=4.3 Hz, 1H), 8.63 (s, 1H), 8.41(d, J=4.3 Hz, 1H), 8.22 (s, 1H), 7.43 (d, J=8.1 Hz, 2H), 7.25 (d, J=8.1Hz, 2H), 5.92-5.76 (m, 1H), 3.89-3.65 (m, 1H), 3.39 (d, J=12.6 Hz, 1H),2.94-2.81 (m, 1H), 2.61 (s, 3H), 1.16 (d, J=6.8 Hz, 6H).

4-[(S)-1-(4-Isopropyl-phenyl)-2-methylamino-ethylamino]-pyrido[3,4-d]pyrimidine-8-carboxylicAcid Amide (40)

Compound 40 was prepared following general synthesis scheme 8 wherein amixture of 4-Hydroxy-pyrido[3,2-d]pyrimidine-8-carboxylamide (G) and4-Hydroxy-pyrido[3,4-d]pyrimidine-8-carboxylamide (H) was reacted withN—[(S)-2-Amino-2-(4-isopropyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamidehydrochloride. The title compound was isolated as the minor product(white solid). LC/MS [365 (M+H)]; ¹H NMR (500 MHz, DMSO-d6) δ 9.14 (s,2H), 8.82-8.58 (m, 2H), 8.40 (s, 1H), 7.82 (s, 1H), 7.42 (d, J=7.8 Hz,2H), 7.26 (d, J=7.9 Hz, 2H), 6.52 (s, 1H), 5.89 (s, 1H), 3.68-3.54 (m,1H), 3.51-3.43 (m, 1H), 2.98-2.78 (m, 1H), 2.65 (s, 3H), 1.17 (d, J=6.8Hz, 6H).

4-[(S)-2-Azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxamide(41)

Compound 41 was prepared following general synthesis scheme 8 wherein4-hydroxy-pyrido[3,2-d]pyrimidine-8-carboxylamide (G) was reacted with(S)-2-(azetidin-1-yl)-1-(4-chloro-3-(trifluoromethyl)phenyl)ethanaminedihydrochloride to give the title compound as a off-white solid. LC/MS[451 (M+H)]; ¹H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.20 (s, 1H),9.01 (d, 1H), 8.56 (d, 1H), 8.39 (dd, 1H), 8.20 (d, 1H), 8.05 (s, 1H),7.80 (d, 1H), 7.68 (d, 1H), 5.38 (t, 1H), 3.11 (ddd, 5H), 2.84 (dd, 1H),1.93 (p, 2H). IC₅₀ p70S6K: 1.6 nM, Akt: 11 nM

4-[(S)-1-(4-Chloro-3-trifluoromethyl-phenyl)-2-methylamino-ethylamino]-pyrido[3,4-d]pyrimidine-8-carboxylicAcid Amide (42)

Compound 42 was prepared following general synthesis scheme 8 wherein amixture of 4-Hydroxy-pyrido[3,2-d]pyrimidine-8-carboxylamide (G) and4-Hydroxy-pyrido[3,4-d]pyrimidine-8-carboxylamide (H) was reacted withN—[(S)-2-Amino-2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamidehydrochloride. LC/MS [425 (M+H)]; ¹H NMR (500 MHz, DMSO-d6) δ 9.92 (s,1H), 9.28 (s, 1H), 9.00 (d, J=4.5 Hz, 1H), 8.55 (s, 1H), 8.38 (d, J=4.5Hz, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.77 (d, J=7.4 Hz, 1H), 7.67 (d,J=8.4 Hz, 1H), 5.64-5.44 (m, 1H), 3.20-3.09 (m, 1H), 3.04-2.88 (m, 1H),2.30 (s, 3H).

4-[(S)-1-(3,4-Bis-trifluoromethyl-phenyl)-2-methylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylamide(43)

Compound 43 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(3,4-bis-trifluoromethyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound as a white solid. LC/MS [459(M+H)]; ¹H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.34 (s, 1H), 9.02 (d,1H), 8.54 (s, 1H), 8.39 (d, 1H), 8.18 (d, 2H), 7.98 (q, 2H), 5.62 (s,1H), 3.16 (dd, 1H), 3.00 (dd, 1H), 2.32 (d, 3H).

4-[(S)-1-(4-Chloro-3-methyl-phenyl)-2-methylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (44)

Compound 44 was prepared following general synthesis scheme 8 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(4-chloro-3-methyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound as a white solid. LC/MS [371(M+H)]; ¹H NMR (500 MHz, DMSO-d6) δ 9.95 (s, 1H), 9.08 (s, 1H), 8.99 (d,J=4.3 Hz, 1H), 8.53 (s, 1H), 8.37 (d, J=4.3 Hz, 1H), 8.17 (s, 1H), 7.43(s, 1H), 7.34 (d, J=8.2 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 5.54-5.26 (m,1H), 3.21-3.03 (m, 1H), 3.00-2.77 (m, 1H), 2.30 (s, 6H), 1.78 (s, 1H).

4-[(S)-1-(4-Chloro-phenyl)-2-methylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (45)

Compound 45 was prepared following general synthesis scheme 8 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(4-chloro-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound as a white solid. LC/MS [357(M+H)].

4-[(S)-2-Azetidin-1-yl-1-(4-chloro-3-methyl-phenyl)-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (46)

Compound 46 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with(S)-2-Azetidin-1-yl-1-(4-chloro-3-methyl-phenyl)-ethylaminedihydrochloride to give the title compound as an off-white solid. LC/MS[397 (M+H)]; ¹H NMR (500 MHz, DMSO-d6) δ 9.95 (s, 1H), 9.01 (s, 1H),8.99 (d, J=4.5 Hz, 1H), 8.53 (s, 1H), 8.37 (d, J=4.5 Hz, 1H), 8.17 (s,1H), 7.45 (s, 1H), 7.39-7.24 (m, 2H), 5.34-5.17 (m, 1H), 3.20-2.98 (m,5H), 2.83-2.71 (m, 1H), 2.29 (s, 3H), 2.01-1.84 (m, 1H).

4-[(S)-2-Azetidin-1-yl-1-(3-chloro-4-cyano-phenyl)-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (47)

Compound 47 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with4-((S)-1-Amino-2-azetidin-1-yl-ethyl)-2-chloro-benzonitrilehydrochloride to give the title compound as a white solid. LC/MS [409(M+H)]; ¹H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.16 (d, 1H), 9.03 (d,1H), 8.56 (s, 1H), 8.40 (d, 1H), 8.18 (s, 1H), 7.93 (d, 1H), 7.66 (d,1H), 5.35 (s, 1H), 3.27-2.97 (m, 2H), 2.88 (d, 2H), 2.01-1.83 (m, 4H).

4-[(S)-2-Azetidin-1-yl-1-(3-difluoromethyl-4-fluoro-phenyl)-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (48)

Compound 48 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with(S)-2-Azetidin-1-yl-1-(3-difluoromethyl-4-fluoro-phenyl)-ethylaminehydrochloride to give the title compound as a white solid. LC/MS [409(M+H)]; ¹H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.09 (d, 1H), 9.02 (d,1H), 8.55 (s, 1H), 8.39 (d, 1H), 8.18 (s, 1H), 7.58 (t, 1H), 7.52 (d,1H), 7.45 (d, 1H), 7.29 (s, 1H), 7.16 (s, 1H), 7.02 (s, 1H), 5.34 (dd,1H), 3.20-3.02 (m, 4H), 2.84 (dd, 2H), 1.99-1.85 (m, 2H).

4-[(S)-1-(4-Fluoro-3-trifluoromethyl-phenyl)-2-methylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (49)

Compound 49 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound as a white solid. LC/MS [409(M+H)]; ¹H NMR (400 MHz, Acetonitrile-d3) δ 10.30 (s, 1H), 8.94 (d, 1H),8.47 (d, 3H), 7.72 (dd, 2H), 7.28 (t, 1H), 6.59 (s, 1H), 5.41 (d, 1H),3.13 (dd, 1H), 3.03 (dd, 1H), 2.38 (s, 3H).

4-[(S)-2-Dimethylamino-1-(4-fluoro-3-trifluoromethyl-phenyl)-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (50)

Compound 50 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with(S)-1-(4-Fluoro-3-trifluoromethyl-phenyl)-N2,N2-dimethyl-ethane-1,2-diaminehydrochloride to give the title compound as a white solid. LC/MS [423(M+H)]; ¹H NMR (400 MHz, Acetonitrile-d3) δ 10.31 (s, 1H), 8.96 (d, 1H),8.55-8.42 (m, 3H), 7.90-7.73 (m, 2H), 7.33 (t, 1H), 6.63 (s, 1H), 5.55(s, 1H), 3.20 (s, 1H), 2.81 (s, 1H), 2.17 (s, 6H).

4-[(S)-1-(3-Difluoromethyl-4-fluoro-phenyl)-2-methylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (51)

Compound 51 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(3-difluoromethyl-4-fluoro-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound as a white solid. LC/MS [391(M+H)].

4-[(S)-1-(4-Fluoro-3-trifluoromethyl-phenyl)-2-isopropylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (52)

Compound 52 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-N-isopropyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound as a white solid. LC/MS [437(M+H)]; ¹H NMR (400 MHz, Acetonitrile-d3) δ 10.31 (s, 1H), 8.93 (d, 1H),8.49 (t, 3H), 7.79-7.64 (m, 2H), 7.28 (t, 1H), 6.59 (s, 1H), 5.38 (s,1H), 3.14 (dt, 2H), 2.89-2.72 (m, 1H), 1.03 (t, 6H).

4-[(S)-1-(4-Chloro-3-fluoro-phenyl)-2-dimethylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (53)

Compound 53 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with(S)-1-(4-Chloro-3-fluoro-phenyl)-N2,N2-dimethyl-ethane-1,2-diaminehydrochloride to give the title compound as a white solid. LC/MS [390(M+H)]; ¹H NMR (400 MHz, Acetonitrile-d3) δ 10.34 (s, 1H), 8.96 (d, 1H),8.49 (d, 2H), 8.35 (s, 1H), 7.46 (t, 1H), 7.35 (d, 1H), 7.28 (d, 1H),6.62 (s, 1H), 5.26 (d, 1H), 2.93 (t, 1H), 2.60 (dd, 1H), 2.29 (s, 6H).

4-[(S)-1-(4-Chloro-3-fluoro-phenyl)-2-isopropylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (54)

Compound 54 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(4-chloro-3-fluoro-phenyl)-ethyl]-N-isopropyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound as a white solid. LC/MS [404(M+H)].

4-[(S)-1-(4-Chloro-3-trifluoromethyl-phenyl)-2-isopropylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (55)

Compound 55 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-N-isopropyl-4-nitro-benzenesulfonamideto give the title compound as a white solid. LC/MS [454 (M+H)]; ¹H NMR(400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.26 (s, 1H), 9.01 (d, 1H), 8.55 (s,1H), 8.38 (d, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.76 (d, 1H), 7.67 (d,1H), 5.47 (s, 1H), 3.15 (d, 1H), 3.02 (s, 1H), 2.80-2.69 (m, 1H), 0.96(dd, 6H).

4-[(S)-2-Ethylamino-1-(4-fluoro-3-trifluoromethyl-phenyl)-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (56)

Compound 56 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-N-ethyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound as a white solid. LC/MS [423(M+H)]; ¹H NMR (400 MHz, DMSO-d6) δ 9.93 (d, 1H), 9.26 (s, 1H), 9.00 (d,1H), 8.54 (s, 1H), 8.37 (d, 1H), 8.16 (d, 1H), 7.92 (dd, 1H), 7.82 (ddd,1H), 7.44 (dd, 1H), 5.51 (m, 1H), 3.17 (dd, 1H), 2.99 (dd, 1H),2.62-2.52 (q, 2H), 0.97 (t, 3H).

4-[(S)-1-(3-Chloro-4-fluoro-phenyl)-2-methylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (57)

Compound 57 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(3-chloro-4-fluoro-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound as a white solid. LC/MS [376(M+H)]; ¹H NMR (400 MHz, Acetonitrile-d3) δ 10.31 (s, 1H), 8.93 (d, 1H),8.46 (dd, 3H), 7.51 (d, 1H), 7.36 (s, 1H), 7.20 (t, 1H), 6.58 (s, 1H),5.34 (dd, 1H), 3.11 (dd, 1H), 3.00 (dd, 1H), 2.37 (s, 3H).

4-[(S)-2-Ethylamino-1-(2,4,5-trifluoro-phenyl)-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (58)

Compound 58 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-N-ethyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound as a white solid. LC/MS [391(M+H)]; ¹H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.13 (s, 1H), 9.02 (d,1H), 8.57 (s, 1H), 8.38 (t, 1H), 8.18 (s, 1H), 7.66 (dd, 1H), 7.53 (td,1H), 5.71 (s, 1H), 3.15 (dd, 1H), 2.95 (dd, 1H), 2.67-2.55 (q, 2H), 0.98(t, 3H).

4-[(S)-1-(3,4-Bis-trifluoromethyl-phenyl)-2-ethylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (59)

Compound 59 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(3,4-bis-trifluoromethyl-phenyl)-ethyl]-N-ethyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound as a white solid. LC/MS [473(M+H)]; ¹H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 9.35 (s, 1H), 9.03 (d,1H), 8.55 (s, 1H), 8.40 (d, 1H), 8.19 (d, 2H), 7.99 (q, 2H), 5.60 (s,1H), 3.25-3.15 (m, 1H), 3.06 (s, 1H), 2.58 (d, 2H), 0.98 (t, 3H).

4-[(S)-2-Methylamino-1-(2,4,5-trifluoro-phenyl)-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (60)

Compound 60 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound as a white solid. LC/MS [377(M+H)].

4-[(S)-1-(3-Chloro-4-fluoro-phenyl)-2-ethylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (61)

Compound 61 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(3-chloro-4-fluoro-phenyl)-ethyl]-N-ethyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound as a white solid. LC/MS [390(M+H)]; ¹H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.16 (s, 1H), 9.00 (d,1H), 8.56 (s, 1H), 8.38 (d, 1H), 8.17 (s, 1H), 7.71 (dd, 1H), 7.52-7.43(m, 1H), 7.35 (t, 1H), 5.44 (s, 1H), 3.16 (dd, 1H), 2.96 (dd, 1H), 2.57(dt, 2H), 0.98 (t, 3H).

4-[(S)-2-Azetidin-1-yl-1-(4-fluoro-3-trifluoromethyl-phenyl)-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (62)

Compound 62 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with(S)-2-Azetidin-1-yl-1-(4-fluoro-3-trifluoromethyl-phenyl)-ethylamine togive the title compound as a white solid. LC/MS [390 (M+H)].

4-[(S)-2-Azetidin-1-yl-1-(3,4-bis-trifluoromethyl-phenyl)-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (63)

Compound 63 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with(S)-2-Azetidin-1-yl-1-(3,4-bis-trifluoromethyl-phenyl)-ethylamine togive the title compound as a white solid. LC/MS [485 (M+H)].

4-[(S)-1-(3-Chloro-phenyl)-2-methylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (64)

Compound 64 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(3-chloro-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound. LC/MS [357 (M+H)] ¹H NMR (400MHz, DMSO-d6) δ 9.96 (s, 1H), 9.20 (br s, 1H), 9.00 (d, 1H), 8.55 (s,1H), 8.39 (d, 1H), 8.20 (s, 1H), 7.56 (m, 1H), 7.47-7.26 (m, 3H), 5.48(s, 1H), 3.16 (dd, 1H), 2.92 (dd, 1H), 2.31 (s, 3H)

4-[(S)-1-(3-Bromo-phenyl)-2-methylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (65)

Compound 65 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(3-bromo-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound. LC/MS [401,403 (M+H)] ¹H NMR(400 MHz, DMSO-d6) δ 9.96 (s, 1H), 9.19 (s, 1H), 9.01 (d, 1H), 8.55 (s,1H), 8.39 (d, 1H), 8.19 (s, 1H), 7.70 (m, 1H), 7.52-7.38 (m, 3H), 7.29(m, 1H), 5.48 (s, 1H), 3.15 (dd, 1H), 2.91 (dd, 1H), 2.31 (s, 3H)

4-[(S)-1-(3-Fluoro-phenyl)-2-methylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (66)

Compound 66 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(3-fluoro-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound. LC/MS [341 (M+H)].

4-[(S)-1-(4-Fluoro-3-methyl-phenyl)-2-methylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (67)

Compound 67 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(4-fluoro-3-methyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamidehydrochloride to give the title compound. LC/MS [355 (M+H)] ¹H NMR (400MHz, DMSO-d6) δ 9.97 (s, 1H), 9.07 (s, 1H), 8.99 (d, 1H), 8.54 (s, 1H),8.38 (d, 1H), 8.17 (s, 1H), 7.38 (m, 1H), 7.30 (m, 1H), 7.07 (m, 1H),5.45 (s, 1H), 3.15 (dd, 1H), 2.89 (dd, 1H), 2.32 (s, 3H), 2.21 (s, 3H).

4-[(S)-2-Azetidin-1-yl-1-(3-fluoro-phenyl)-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (68)

Compound 68 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with(S)-2-azetidin-1-yl-1-(3-fluoro-phenyl)-ethylamine hydrochloride to givethe title compound. LC/MS [367 (M+H)] ¹H NMR (400 MHz, DMSO-d6) δ 9.94(s, 1H), 9.07 (d, 1H), 9.01 (d, 1H), 8.56 (s, 1H), 8.39 (d, 1H), 8.17(s, 1H), 7.34 (m, 3H), 7.07 (m, 1H), 5.36 (m, 1H), 3.13 (m, 4H), 2.86(m, 1H), 1.96 (m, 2H).

4-[(S)-1-(4-Chloro-3-trifluoromethyl-phenyl)-2-(3-fluoro-azetidin-1-yl)-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (69)

Compound 69 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with(S)-1-(4-chloro-3-trifluoromethyl-phenyl)-2-(3-fluoro-azetidin-1-yl)-ethylaminehydrochloride to give the title compound. LC/MS [469 (M+H)] ¹H NMR (400MHz, DMSO-d6) δ 9.92 (s, 1H), 9.26 (d, 1H), 9.01 (d, 1H), 8.57 (s, 1H),8.39 (d, 1H), 8.17 (s, 1H), 8.08 (s, 1H), 7.82 (m, 1H), 7.68 (m, 1H),5.45 (m, 1H), 5.12 (m, 1H), 3.59 (m, 2H), 3.21 (m, 2H), 2.95 (m, 5.6 Hz,1H).

4-[(S)-1-(4-Chloro-3-trifluoromethyl-phenyl)-2-(3-hydroxy-azetidin-1-yl)-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (70)

Compound 70 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with(S)-1-(4-chloro-3-trifluoromethyl-phenyl)-2-(3-hydroxy-azetidin-1-yl)-ethylaminehydrochloride to give the title compound. LC/MS [467 (M+H)].

4-[(R)-2-Azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylamide(71)

Compound 71 was prepared following general synthesis scheme 7 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with(R)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylaminehydrochloride to give the title compound. LC/MS [451 (M+H)].

4-[(S)-1-(4-Chloro-3-trifluoromethyl-phenyl)-2-methylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (72)

Compound 72 was prepared following general synthesis scheme 10 whereinmethyl 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxylate (I) was reactedwithN—[(S)-2-Amino-2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamideto give the title compound. LC/MS [425 (M+H)]; ¹H NMR (400 MHz, DMSO-d6)δ 9.93 (s, 1H), 9.29 (s, 1H), 9.00 (d, J=4.6 Hz, 1H), 8.54 (s, 1H), 8.38(d, J=4.5 Hz, 1H), 8.19 (s, 1H), 8.00 (s, 1H), 7.77 (d, J=8.4 Hz, 1H),7.66 (d, J=8.3 Hz, 1H), 5.53 (s, 1H), 3.13 (dd, J=12.3, 8.3 Hz, 1H),2.94 (dd, J=12.4, 5.8 Hz, 1H), 2.29 (s, 3H), 1.92 (s, 1H).

4-[(S)-2-Azetidin-1-yl-1-(3-chloro4-trifluoromethoxy-phenyl)-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylamide(73)

Compound 73 was prepared following general synthesis scheme 11 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with(S)-2-azetidin-1-yl-1-(-(3-chloro4-trifluoromethoxy-phenyl)-ethylaminehydrochloride to give 33 mg of the title compound as a white solid.LC/MS [467 (M+H)]; ¹H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 9.12 (d,J=8.1 Hz, 1H), 9.00 (d, J=4.5 Hz, 1H), 8.56 (s, 1H), 8.38 (d, J=4.5 Hz,1H), 8.17 (s, 1H), 7.85 (s, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.51 (d, J=8.6Hz, 1H), 5.33 (q, J=7.7 Hz, 1H), 3.13 (hept, J=6.7 Hz, 4H), 3.09-2.99(m, 1H), 2.82 (dd, J=12.0, 5.8 Hz, 1H), 1.92 (p, J=7.0 Hz, 2H).

4-[(S)-1-(3-Chloro-4-trifluoromethoxy-phenyl)-2-methylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylamide(74)

Compound 74 was prepared following general synthesis scheme 11 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-amino-2-(3-chloro4-trifluoromethoxy-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamidehydrochloride to give 57 mg of the title compound as a white solid.LC/MS [441 (M+H)])]; 1H NMR (400 MHz, DMSO-d6) δ 9.92 (d, J=3.5 Hz, 1H),9.35-9.22 (m, 1H), 9.01 (d, J=4.4 Hz, 1H), 8.57 (s, 1H), 8.39 (d, J=4.5Hz, 1H), 8.18 (d, J=3.9 Hz, 1H), 7.83 (d, J=1.9 Hz, 1H), 7.61-7.47 (m,2H), 5.60 (s, 1H), 3.26 (d, J=11.3 Hz, 1H), 3.05 (d, J=12.4 Hz, 1H),2.37 (s, 3H).

4-[(S)-1-(3,4-Dichloro-phenyl)-2-methylamino-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylamide(75)

Compound 75 was prepared following general synthesis scheme 11 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-amino-2-(3,4-dichloro-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide.LC/MS [391 (M+H)], ¹H NMR (400 MHz, DMSO-d6) δ 9.94 (d, 1H), 9.17 (d,1H), 9.00 (d, 1H), 8.55 (s, 1H), 8.38 (d, 1H), 8.17 (d, 1H), 7.76 (d,1H), 7.58 (d, 1H), 7.45 (dd, 1H), 5.46 (s, 1H), 3.13 (dd, 1H), 2.92 (dd,1H), 2.30 (s, 3H).

4-[(S)-2-Methylamino-1-(4-methyl-3-trifluoromethyl-phenyl)-ethylamino]-pyrido[3,2-d]pyrimidine-8-carboxylicAcid Amide (76)

Compound 76 was prepared following general synthetic scheme 11 wherein4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted withN—[(S)-2-Amino-2-(4-methyl-3-trifluoromethyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide.LC-MS [405 (M+1)]; ¹H NMR (400 MHz, DMSO-d6) δ 9.95 (d, J=3.4 Hz, 1H),9.21 (d, J=8.5 Hz, 1H), 9.00 (d, J=4.6 Hz, 1H), 8.54 (s, 1H), 8.38 (d,J=4.5 Hz, 1H), 8.16 (d, J=3.5 Hz, 1H), 7.80 (s, 1H), 7.63 (d, J=7.9 Hz,1H), 7.38 (d, J=8.1 Hz, 1H), 5.51 (s, 1H), 3.15 (dd, J=12.4, 8.4 Hz,1H), 2.92 (dd, J=12.3, 5.5 Hz, 1H), 2.40 (s, 4H), 2.30 (s, 3H).

Example 3: p70S6K Enzyme Assay

p70S6K inhibitor compounds were diluted and plated in 96 well plates. Areaction mixture including the following components were then added tothe compound plate to initiate the enzyme reaction: p70S6K (3 nM, T412Emutant, Millipore) was mixed with 24 μM ATP in an assay buffercontaining 100 mM Hepes (pH 7.5), 5 mM MgCl₂, 1 mM DTT, 0.015% Brij and1 μM of the substrate peptide FITC-AHA-AKRRRLSSLRA-OH (derived from theS6 ribosomal protein sequence, FITC=fluorescein isothiocyanate,AHA=6-aminohexanoic acid). The reaction was incubated for 90 min at 25°C., before the addition of 10 mM EDTA to stop the reaction. Theproportion of substrate and product (phosphorylated) peptide wasanalyzed on a Caliper Life Sciences Lab Chip 3000, using a pressure of−1.4 psi, and upstream and downstream voltages of −3000 and −700,respectively. Product peaks were resolved before substrate peaks on theresulting chromatograms. To assess the inhibitory potential of thecompounds, IC₅₀ values were determined, as shown above.

Example 4: AKT/PKB Kinase Assay

In order to measure AKT inhibition in the Caliper Life Sciences LC3000,a TTP Mosquito liquid handling instrument was used to place 125 nl ofthe appropriate concentration of inhibitor in 100% DMSO (for a doseresponse curve calculation) into each well of a 384-well plate. To thisreaction, the following components were added to a final volume of 12.5μl:

-   -   0.1 ng/μl His-AKT (Full Length) (Invitrogen, Part # P2999, Lot        #641228C);    -   160 μM ATP (Fluka, 02055);    -   1 mM DTT (Sigma, D0632);    -   1 mM MgCl₂ (Sigma, M1028);    -   1 μM substrate peptide (sequence FITC-AHA-GRPRTSSFAEG-NH₂),        synthesized by    -   Tufts Peptide Synthesis service;    -   100 mM HEPES pH 7.5 (Calbiochem, 391338); and    -   0.015% Brij-35 (Sigma, B4184).

The reaction was incubated for 90 min at 25° C., and then stopped by theaddition of 70 μl of Stop buffer (100 mM HEPES pH 7.5, 0.015% Brij-35,10 mM EDTA (Sigma, E7889)). The plate was read on a Caliper LC 3000 inan Off-Chip mobility shift assay format, using the following parametersfor a 12-sipper chip: screening pressure −2.3 psi, upstream voltage−500, and downstream voltage −3000. These conditions causeunphosphorylated substrate and phosphorylated product peptide to resolveas separate peaks allowing direct measurement of percentage ofconversion of substrate to product. The percent conversion was plottedagainst concentration of inhibitor to produce a sigmoidal dose responsecurve, from which an IC₅₀ was calculated.

The values for the p70S6K and AKT enzyme inhibition assays for selectedcompounds set out in the Experimental section are presented in Table 1.The data are presented as follows:

+++++: <25 nM;

++++: 25-100 nM;

+++: 101 nM-500 nM;

++: 501 nM-1000 nM;

+: >1 μM.

TABLE 1 p70S6K Enzyme Inhibition by Compounds Described by Formula (I)IC₅₀ IC₅₀ Compound p70S6K (nM) AKT (nM) 1 +++ + 2 +++++ + 3 + + 4+++++ + 5 + + 6 ++ + 7 + + 8 ++++ + 9 ++ + 10 +++++ +++ 11 ++++ +++ 12+++++ +++++ 13 +++++ +++++ 14 +++++ +++++ 15 +++++ +++++ 16 +++++ +++++17 ++++ +++ 18 +++++ +++ 19 + + 20 +++++ ++++ 21 +++++ +++++ 22 ++++++++ 23 ++++ +++ 24 25 +++++ ++ 26 +++++ +++++ 27 +++++ +++ 28 ++++++++++ 29 +++++ ++++ 30 +++++ ++++ 31 ++++ + 32 +++++ +++ 33 +++++ ++++34 ++++ +++ 35 +++++ ++++ 36 +++++ +++ 37 +++++ ++ 38 +++++ ++++ 39+++++ +++ 40 ++++ + 41 +++++ +++++ 42 +++++ +++++ 43 +++++ +++++ 44+++++ +++++ 45 +++++ ++++ 46 +++++ +++++ 47 +++++ +++++ 48 +++++ +++++49 +++++ +++++ 50 +++++ ++++ 51 +++++ +++++ 52 ++++ +++ 53 +++++ ++++ 54++++ +++ 55 +++ +++ 56 +++++ ++++ 57 +++++ +++++ 58 ++++ +++ 59 ++++++++++ 60 ++++ ++++ 61 +++++ ++++ 62 +++++ +++++ 63 +++++ +++++ 64 ++++++++++ 65 +++++ +++++ 66 +++++ +++++ 67 +++++ +++++ 68 +++++ ++++ 69+++++ ++++ 70 +++++ ++++ 71 ++ + 72 +++++ +++++ 73 +++++ ++++ 74 +++++++++ 75 +++++ +++++ 76 +++++ +++++

Example 5: Pharmaceutical Preparations

(A) Injection vials: A solution of 100 g of an active ingredientaccording to the invention and 5 g of disodium hydrogen phosphate in 3 lof bidistilled water are adjusted to pH 6.5 using 2 N hydrochloric acid,sterile filtered, are transferred into injection vials, are lyophilizedunder sterile conditions and are sealed under sterile conditions. Eachinjection vial contains 5 mg of active ingredient.(B) Suppositories: A mixture of 20 g of an active ingredient accordingto the invention is melted with 100 g of soy lecithin and 1400 g ofcocoa butter, is poured into moulds and is allowed to cool. Eachsuppository contains 20 mg of active ingredient.(C) Solution: A solution is prepared from 1 g of an active ingredientaccording to the invention, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g ofNa₂HPO₄.12H₂O and 0.1 g of benzalkonium chloride in 940 ml ofbidistilled water. The pH is adjusted to 6.8, and the solution is madeup to 1 l and sterilized by irradiation. This solution could be used inthe form of eye drops.(D) Ointment: 500 mg of an active ingredient according to the inventionare mixed with 99.5 g of Vaseline under aseptic conditions.(E) Tablets: A mixture of 1 kg of an active ingredient according to theinvention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and0.1 kg of magnesium stearate is pressed to give tablets in aconventional manner in such a way that each tablet contains 10 mg ofactive ingredient.(F) Coated tablets: Tablets are pressed analogously to Example E and aresubsequently coated in a conventional manner with a coating of sucrose,potato starch, talc, tragacanth and dye.(G) Capsules: 2 kg of an active ingredient according to the inventionare introduced into hard gelatin capsules in a conventional manner insuch a way that each capsule contains 20 mg of the active ingredient.(H) Ampoules: A solution of 1 kg of an active ingredient according tothe invention in 60 l of bidistilled water is sterile filtered, istransferred into ampoules, is lyophilized under sterile conditions andis sealed under sterile conditions. Each ampoule contains 10 mg ofactive ingredient.(I) Inhalation spray: 14 g of an active ingredient according to theinvention are dissolved in 10 l of isotonic NaCl solution, and thesolution is transferred into commercially available spray containerswith a pump mechanism. The solution could be sprayed into the mouth ornose. One spray shot (about 0.1 ml) corresponds to a dose of about 0.14mg.

The invention claimed is:
 1. A compound of formula (I):

wherein: W¹ is CH; W² is CH; W³ is N; and W⁴ is CH; or W¹ is CH; W² isCH; W³ is CH; and W⁴ is N; R¹ is Ar or Het¹; each of R², R⁴, and R⁵ isindependently Y; R³ is Y or —(CH₂)_(p)—NR⁴R⁵; or R² and R³ together withthe atoms to which each is attached, may form —(CH₂)_(n)—NY—(CH₂)_(p);or R⁴ and R⁵ together with the atoms to which each is attached, may form—(CY₂)_(q)—; each Y is independently H or A; each A is independentlyunbranched or branched alkyl having 1-10 C atoms, in which 1-7 H atomscan be replaced independently from one another by Hal; Ar is anunsaturated or aromatic monocyclic or bicyclic carbocycle having 3-10 Catoms, which can be substituted by at least one substituent selectedfrom the group consisting of Hal, A, OY, CN, COY, COOY, CONYY, NYCOY,NYCONYY, SO₂Y, SO₂NYY, NYSO₂Y, NYY, NO₂, OCN, SCN, SH, phenyl and Het¹,where the phenyl is optionally substituted by Hal, A, OY, CN, COY, COOY,CONYY, NYCOY, NYCONYY, SO₂Y, SO₂NYY, NYSO₂Y, NYY, NO₂, OCN, SCN or SH;each Het¹ is independently an unsaturated or aromatic monocyclic orbicyclic heterocycle having 2-10 C atoms and 1-4 N, O and/or S atoms,which can be substituted by at least one substituent selected from thegroup consisting of Hal, A, OY, CN, COY, COOY, CONYY, NYCOY, NYCONYY,SO₂Y, SO₂NYY, NYSO₂Y, NYY, NO₂, OCN, SCN, SH, phenyl and Het², where thephenyl is optionally substituted by Hal, A, OY, CN, COY, COOY, CONYY,NYCOY, NYCONYY, SO₂Y, SO₂NYY, NYSO₂Y, NYY, NO₂, OCN, SCN or SH; Het² issaturated, unsaturated or aromatic monocyclic 5-6-membered heterocyclehaving 2-5 C atoms and 1-3 N, O and/or S atoms, which is optionallysubstituted by Hal, A, OY, CN, COY, COOY, CONYY, NYCOY, NYCONYY, SO₂Y,SO₂NYY, NYSO₂Y, NYY, NO₂, OCN, SCN or SH; each Hal is independently F,Cl, Br or I; m is 0 or 1; each of n and p is independently 0, 1, 2 or 3;and q is 2, 3, 4, 5 or 6; and/or a physiologically acceptable saltthereof.
 2. The compound according to claim 1, wherein R¹ is phenyl orpyridyl, each of which is optionally substituted.
 3. The compoundaccording to claim 2, wherein R¹ is


4. The compound according to claim 3, wherein R¹ is


5. The compound according to claim 1, wherein R³ is H or—(CH₂)_(p)—NR⁴R⁵.
 6. The compound according to claim 5, wherein R³ is H,


7. The compound according to claim 6, wherein R³ is H,


8. The compound according to claim 1, wherein R² and R³ together withthe atoms to which each is attached, is


9. The compound according to claim 1, which is selected from the groupconsisting of:(R)-4-((2-(azetidin-1-yl)-1-(4-chloro-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidine-8-carboxamide(19);(S)-4-((2-(azetidin-1-yl)-1-(4-chloro-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[4,3-d]pyrimidine-8-carboxamide(20);4-[(S)-1-(4-Isopropyl-phenyl)-2-methylamino-ethylamino]-pyrido[3,4-d]pyrimidine-8-carboxylicacid amide (40); and4-[(S)-1-(4-Chloro-3-trifluoromethyl-phenyl)-2-methylamino-ethylamino]-pyrido[3,4-d]pyrimidine-8-carboxylicacid amide (42).
 10. A pharmaceutical composition comprising as activeingredient at least one compound according to claim 1, and/or aphysiologically acceptable salt thereof, together with at least onepharmaceutically tolerable excipient, and optionally in combination withone or more further active ingredients.
 11. A method for inhibitingp70S6K in a system expressing p70S6K, wherein the system is contactedwith at least one compound according to claim 1, and/or aphysiologically acceptable salt thereof.
 12. A method for treatingbreast cancer, bladder cancer, pancreatic cancer, renal cancer, lungcancer or neuroblastoma in a subject, comprising administering to thesubject at least one compound according to claim 1, and/or aphysiologically acceptable salt thereof.